US20110092510A1 - Dpp-iv inhibitors for use in the treatment of nafld - Google Patents
Dpp-iv inhibitors for use in the treatment of nafld Download PDFInfo
- Publication number
- US20110092510A1 US20110092510A1 US12/995,474 US99547409A US2011092510A1 US 20110092510 A1 US20110092510 A1 US 20110092510A1 US 99547409 A US99547409 A US 99547409A US 2011092510 A1 US2011092510 A1 US 2011092510A1
- Authority
- US
- United States
- Prior art keywords
- methyl
- amino
- active substances
- piperidin
- dpp
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 0 [1*]N1C(=O)C2=C(N=C([2*])N2CC#CC)N(C)C1=O Chemical compound [1*]N1C(=O)C2=C(N=C([2*])N2CC#CC)N(C)C1=O 0.000 description 8
- BNPBEDWUQOSRHB-UHFFFAOYSA-N CC#CCN1C(N(C)CC(C)(C)N)=NC2=C1C(=O)N(CC1=NC3=C(C=CC=C3)C(C)=N1)C(=O)N2C Chemical compound CC#CCN1C(N(C)CC(C)(C)N)=NC2=C1C(=O)N(CC1=NC3=C(C=CC=C3)C(C)=N1)C(=O)N2C BNPBEDWUQOSRHB-UHFFFAOYSA-N 0.000 description 2
- ZOTODWFVYUPZFO-GOSISDBHSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=C(C#N)C=CC=C1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=C(C#N)C=CC=C1)C(=O)N2C ZOTODWFVYUPZFO-GOSISDBHSA-N 0.000 description 2
- LTXREWYXXSTFRX-QGZVFWFLSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CC=C3C(C)=N1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CC=C3C(C)=N1)C(=O)N2C LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 2
- ARGSUQOFWVJLEG-QGZVFWFLSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CN=C3C(C)=C1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CN=C3C(C)=C1)C(=O)N2C ARGSUQOFWVJLEG-QGZVFWFLSA-N 0.000 description 2
- OWVQLTBTGFYAHU-HNNXBMFYSA-N CC#CCN1C(N(C)C[C@H](C)N)=NC2=C1C(=O)N(CC1=NC3=C(C=CC=C3)C(C)=N1)C(=O)N2C Chemical compound CC#CCN1C(N(C)C[C@H](C)N)=NC2=C1C(=O)N(CC1=NC3=C(C=CC=C3)C(C)=N1)C(=O)N2C OWVQLTBTGFYAHU-HNNXBMFYSA-N 0.000 description 1
- HDARIOSGMVVPLE-LJQANCHMSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=C(C#N)C=C3C=CC=CC3=N1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=C(C#N)C=C3C=CC=CC3=N1)C(=O)N2C HDARIOSGMVVPLE-LJQANCHMSA-N 0.000 description 1
- GFMVACPPQCXLGW-QGZVFWFLSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=CC3=NC=CN=C3C=C1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=CC3=NC=CN=C3C=C1)C(=O)N2C GFMVACPPQCXLGW-QGZVFWFLSA-N 0.000 description 1
- ONMDRNPIEXAJEZ-MRXNPFEDSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC(C)=CC(C)=N1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC(C)=CC(C)=N1)C(=O)N2C ONMDRNPIEXAJEZ-MRXNPFEDSA-N 0.000 description 1
- HAKJUVBTRWXTRU-QGZVFWFLSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CC=C3C(C)=N1)N=C2 Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CC=C3C(C)=N1)N=C2 HAKJUVBTRWXTRU-QGZVFWFLSA-N 0.000 description 1
- ILTRPILDWNCOMQ-QGZVFWFLSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CC=C3C=N1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC3=CC=CC=C3C=N1)C(=O)N2C ILTRPILDWNCOMQ-QGZVFWFLSA-N 0.000 description 1
- YLTXBUGZVMPESA-OAHLLOKOSA-N CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC=CC(C)=N1)C(=O)N2C Chemical compound CC#CCN1C(N2CCC[C@@H](N)C2)=NC2=C1C(=O)N(CC1=NC=CC(C)=N1)C(=O)N2C YLTXBUGZVMPESA-OAHLLOKOSA-N 0.000 description 1
- UCODEUPVRWMMQA-SNVBAGLBSA-N CC(F)(F)C1=NN=C2CN(C(=O)C[C@H](N)CC3=C(F)C=C(F)C(F)=C3)CCN21 Chemical compound CC(F)(F)C1=NN=C2CN(C(=O)C[C@H](N)CC3=C(F)C=C(F)C(F)=C3)CCN21 UCODEUPVRWMMQA-SNVBAGLBSA-N 0.000 description 1
- IWYJYHUNXVAVAA-OAHLLOKOSA-N CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C#N)C=CC(F)=C2)C1=O Chemical compound CN1C(=O)C=C(N2CCC[C@@H](N)C2)N(CC2=C(C#N)C=CC(F)=C2)C1=O IWYJYHUNXVAVAA-OAHLLOKOSA-N 0.000 description 1
- NVSWJKWHLUTHLP-CPJSRVTESA-N C[C@@H](CC1(C2=NN=NN2)C2=CC=C(C(=O)N(C)C)C=C2CCC2=C1C=CC(C(=O)N(C)C)=C2)NCC(=O)N1CCC[C@H]1C#N Chemical compound C[C@@H](CC1(C2=NN=NN2)C2=CC=C(C(=O)N(C)C)C=C2CCC2=C1C=CC(C(=O)N(C)C)=C2)NCC(=O)N1CCC[C@H]1C#N NVSWJKWHLUTHLP-CPJSRVTESA-N 0.000 description 1
- CDVDVOFWUQKQDH-CQSZACIVSA-N C[C@@H]1CCCN(C2=CC(=O)N(C)C(=O)N2CC2=C(C#N)C=CC=C2)C1 Chemical compound C[C@@H]1CCCN(C2=CC(=O)N(C)C(=O)N2CC2=C(C#N)C=CC=C2)C1 CDVDVOFWUQKQDH-CQSZACIVSA-N 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N N#C[C@@H]1CCCN1C(=O)CNC12CC3CC(CC(O)(C3)C1)C2 Chemical compound N#C[C@@H]1CCCN1C(=O)CNC12CC3CC(CC(O)(C3)C1)C2 SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- AUWVIZIUGLWUDZ-AJNGGQMLSA-N N#C[C@@H]1C[C@H](F)CN1C(=O)CC[C@@H]1CC[C@H](CN2C=NC=N2)C1 Chemical compound N#C[C@@H]1C[C@H](F)CN1C(=O)CC[C@@H]1CC[C@H](CN2C=NC=N2)C1 AUWVIZIUGLWUDZ-AJNGGQMLSA-N 0.000 description 1
- UOCHFMVPMIYRHJ-QWRGUYRKSA-N N[C@H]1CN(C2=NC=NC(N3CCC(F)(F)C3)=N2)C[C@@H]1N1CC(F)(F)CCC1=O Chemical compound N[C@H]1CN(C2=NC=NC(N3CCC(F)(F)C3)=N2)C[C@@H]1N1CC(F)(F)CCC1=O UOCHFMVPMIYRHJ-QWRGUYRKSA-N 0.000 description 1
- GUYMHFIHHOEFOA-ZCPGHIKRSA-N [H][C@@]12C[C@H](N)[C@@H](N3C[C@@H](CF)CC3=O)CN1CCC1=CC(OC)=C(OC)C=C12 Chemical compound [H][C@@]12C[C@H](N)[C@@H](N3C[C@@H](CF)CC3=O)CN1CCC1=CC(OC)=C(OC)C=C12 GUYMHFIHHOEFOA-ZCPGHIKRSA-N 0.000 description 1
- QGJUIPDUBHWZPV-SGTAVMJGSA-N [H][C@]12C[C@@]1([H])C[C@@H](C#N)N2C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2 Chemical compound [H][C@]12C[C@@]1([H])C[C@@H](C#N)N2C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4196—1,2,4-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
Definitions
- the present invention relates to certain DPP-4 inhibitors for treating and/or preventing non alcoholic fatty liver diseases (NAFLD) and to the use of these DPP-4 inhibitors in treating and/or preventing NAFLD and/or diseases related or associated therewith.
- the invention also relates to combinations of certain DPP-4 inhibitors with other active substances for treating and/or preventing NAFLD and to the use of combinations of these DPP-4 inhibitors with other active substances for treating and/or preventing NAFLD.
- Pharmaceutical compositions for use in the treatment and/or prevention of non alcoholic fatty liver diseases (NAFLD) comprising a DPP-4 inhibitor as defined herein optionally together with one or more other active substances are also contemplated.
- NASH non-alcoholic fatty liver diseases
- NASH inflammatory steatohepatitis
- McCullough 2006 The spectrum of fatty liver diseases associated with metabolic determinants and not resulting from alcohol (NAFLD, non-alcoholic fatty liver diseases) extends from simple hepatic steatosis through inflammatory steatohepatitis (NASH, non-alcoholic steatohepatitis) to liver fibrosis and cirrhosis, as well as, in some cases, hepatocellular carcinomas.
- NASH is the most severe form of NAFLD and recent data indicate prevalences for NASH and NAFLD in the range of 17-33% (in US).
- McCullough 2006 The spectrum of fatty liver diseases associated with metabolic determinants and not resulting from alcohol (NAFLD, non-alcoholic fatty liver diseases) extends from simple hepatic steatosis through inflammatory steatohepatitis (NASH, non-alcoholic steatohepatitis) to liver
- the underlying pathophysiological mechanisms of NAFLD and NASH are currently tried to be explained by the first and second hit theory.
- extra-hepatic e.g. increased free fatty acid influx, insulin resistance, fasting, low levels of adiponectin
- intra-hepatic e.g. decreased capacity to secrete VLDL, decreased ⁇ -oxidation
- the first hit leads to hepatic steatosis and predisposes and triggers the second hit for an inflammatory event.
- ROS reactive oxygen species
- pro-inflammatory cytokines like TNF-a are discussed to promote inflammation.
- NASH and NAFLD are rather conservative comprising diet and exercise and weight control. Further, NAFLD and particularly NASH is also associated with an increased risk for endothelial dysfunction and cardiovascular risk, especially over long term. Thus, there is still a high unmet need and a high demand of novel and efficacious medicaments for the treatment of NAFLD and NASH.
- Balaban et al. focused on the role of DPP-4 expression in NASH patients and correlated DPP-4 intensity of immunostaining with histopathological grade of hepatosteatosis and thus, providing additional evidence for the use of DPP-4 inhibitors in this indication.
- the enzyme DPP-4 also known as CD26 is a serine protease known to lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins having at their N-terminal end a prolin or alanin residue. Due to this property DPP-4 inhibitors interfere with the plasma level of bioactive peptides including the peptide GLP-1 and are considered to be promising drugs for the treatment of diabetes mellitus.
- DPP-4 inhibitors and their uses are disclosed in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 or WO2007/014886; or in WO 2004/050658, WO 2004/111051, WO 2005/058901 or WO 2005/097798; or in WO 2006/068163, WO 2007/071738 or WO 2008/017670; or in WO 2007/128721 or WO 2007/128761.
- DPP-4 inhibitors As further DPP-4 inhibitors the following compounds can be mentioned:
- Sitagliptin (MK-0431) having the structural formula A below is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, also named (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,
- sitagliptin is in the form of its dihydrogenphosphate salt, i.e. sitagliptin phosphate.
- sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate.
- a class of this embodiment refers to sitagliptin phosphate monohydrate.
- Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and in WO 2007/050485. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- a tablet formulation for sitagliptin is commercially available under the trade name Januvia®.
- a tablet formulation for sitagliptin/metformin combination is commercially available under the trade name Janumet®.
- Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063 and in Example 1 of WO 00/34241. Specific salts of vildagliptin are disclosed in WO 2007/019255. A crystalline form of vildagliptin as well as a vildagliptin tablet formulation are disclosed in WO 2006/078593. Vildagliptin can be formulated as described in WO 00/34241 or in WO 2005/067976. A modified release vildagliptin formulation is described in WO 2006/135723. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- a tablet formulation for vildagliptin is commercially available under the trade name Galvus®.
- a tablet formulation for vildagliptin/metformin combination is commercially available under the trade name Eucreas®.
- Saxagliptin (BMS-477118) having the structural formula C below is (1S,3S,5S)-2- ⁇ (2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl ⁇ -2-azabicyclo[3.1.0]hexane-3-carbonitrile, also named (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,
- Saxagliptin is specifically disclosed in U.S. Pat. No. 6,395,767 and in Example 60 of WO 01/68603.
- saxagliptin is in the form of its HCl salt or its mono-benzoate salt as disclosed in WO 2004/052850.
- saxagliptin is in the form of the free base.
- saxagliptin is in the form of the monohydrate of the free base as disclosed in WO 2004/052850. Crystalline forms of the HCl salt and the free base of saxagliptin are disclosed in WO 2008/131149.
- a process for preparing saxagliptin is also disclosed in WO 2005/106011 and WO 2005/115982.
- Saxagliptin can be formulated in a tablet as described in WO 2005/117841.
- a process to manufacture, to formulate or to use this compound or a salt thereof reference is thus made to these documents.
- Alogliptin (SYR-322) having the structural formula E below is 2-( ⁇ 6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl ⁇ methyl)benzonitrile
- Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 and in WO 2005/095381.
- alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt each as disclosed in WO 2007/035629.
- a class of this embodiment refers to alogliptin benzoate.
- Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372.
- a process for preparing alogliptin is disclosed in WO 2007/112368 and, specifically, in WO 2007/035629.
- Alogliptin (namely its benzoate salt) can be formulated in a tablet and administered as described in WO 2007/033266.
- Formulations of Aloglipitin with metformin or pioglitazone are described in WO 2008/093882 or WO 2009/011451, respectively.
- WO 2008/093882 for details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- This compound and methods for its preparation are disclosed in WO 2005/000848.
- a process for preparing this compound is also disclosed in WO 2008/031749, WO 2008/031750 and WO2008/055814.
- This compound can be formulated in a pharmaceutical composition as described in WO 2007/017423.
- WO 2007/017423 For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- DPP-4 inhibitors as defined herein have surprising and particularly advantageous properties, which make them particularly suitable for treating and/or preventing (including preventing, slowing, delaying and/or reversing the progression or reducing the occurrence or delaying the onset) of non alcoholic fatty liver disease (NAFLD) including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis, and/or diseases related therewith (such as e.g. diabetes, insulin insensitivity, hepatic glucose overproduction and/or metabolic syndrome) or associated therewith (such as e.g. cardiovascular disease and/or atherosclerosis or other (cardio)metabolic disorders), and thus for preventing liver cirrhosis (irreversible advanced scarring of the liver) and/or hepatocellular carcinomas.
- NAFLD non alcoholic fatty liver disease
- NASH non-alcoholic steatohepatitis
- diseases related therewith such as e.g. diabetes, insulin insensitivity
- the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of non alcoholic fatty liver disease (NAFLD).
- NAFLD non alcoholic fatty liver disease
- the present invention further provides a DPP-4 inhibitor as defined herein for use in improving insulin sensitivity.
- the present invention further provides a DPP-4 inhibitor as defined herein for use in decreasing glucose production in the liver.
- the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of insulin resistance and/or insulin resistance syndrome.
- the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of metabolic syndrome.
- the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of one or more of the features associated with the metabolic syndrome, such as e.g. NAFLD/NASH, (central) obesity, diabetes, dyslipidemia, hypertension and/or atherosclerotic (cardio)vascular disease or damages.
- a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of one or more of the features associated with the metabolic syndrome, such as e.g. NAFLD/NASH, (central) obesity, diabetes, dyslipidemia, hypertension and/or atherosclerotic (cardio)vascular disease or damages.
- the present invention further provides a DPP-4 inhibitor as defined herein for use in preventing and/or reducing the risk of adverse effects associated with existing therapies of NAFLD/NASH (e.g. using TZD and/or metformin).
- the present invention further provides a DPP-4 inhibitor as defined herein for reducing the risk of endothelial dysfunction and/or cardiovascular disease or events, e.g. while treating NAFLD/NASH.
- the present invention provides a DPP-4 inhibitor as defined herein for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight or positively influencing body fat distribution.
- the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of obesity, especially of severe or extreme obesity (e.g. class II or III), e.g. with a BMI ⁇ 35 or even ⁇ 40 kg/m 2 (or ⁇ 30 kg/m 2 for Japanese patients), particularly abdominal and/or visceral obesity.
- severe or extreme obesity e.g. class II or III
- BMI ⁇ 35 or even ⁇ 40 kg/m 2 or ⁇ 30 kg/m 2 for Japanese patients
- abdominal and/or visceral obesity especially obesity, especially of severe or extreme obesity (e.g. class II or III), e.g. with a BMI ⁇ 35 or even ⁇ 40 kg/m 2 (or ⁇ 30 kg/m 2 for Japanese patients), particularly abdominal and/or visceral obesity.
- the present invention further provides a DPP-4 inhibitor as defined herein for treating and/or preventing (including reducing the risk of developing or progressing) NAFLD/NASH and/or diseases or disorders related or associated therewith, particularly in patients with or at risk of NAFLD/NASH, such as e.g. those patients having one or more disorders selected from NAFLD, metabolic syndrome, insulin resistance, IGT, IFG, overweight, obesity (e.g. BMI ⁇ 25-30 kg/m 2 , waist circumference >88 (women)—102 (men) cm, and/or waist:hip ratio >0.85 (women)—0.9 (men), particularly visceral and/or abdominal obesity), dyslipidemia (including hyperlipidemia, particularly hypertriglyceridemia (e.g.
- blood triglyceride level ⁇ 150 mg/dL) and/or hypoHDLemia e.g. blood HDL cholesterol level ⁇ 40 (men)—50 (women) mg/dL
- diabetes particularly type 2 diabetes
- hypertension e.g. ⁇ 130/ ⁇ 85 mmHg
- hyperglycemia hyperinsulinemia, hyperuricemia, severe sleep apnoe, polycystic ovary syndrome, and chronic hepatitis C infection; particularly including elderly patients >45 years.
- the present invention further provides a DPP-4 inhibitor as defined herein for treating and/or preventing (including reducing the risk of developing or progressing) metabolic disorders or diseases, especially diabetes (particularly type 2 diabetes), in patients having NAFLD/NASH.
- a DPP-4 inhibitor as defined herein for the manufacture of a medicament for one or more of the following purposes:
- the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of fibrosis, such as e.g. fibrosis of the liver, lung, skin, heart or kidney.
- fibrosis such as e.g. fibrosis of the liver, lung, skin, heart or kidney.
- the present invention further provides the use of a DPP-4 inhibitor as defined herein for the manufacture of a pharmaceutical composition for treatment and/or prevention of those diseases given hereinabove or hereinbelow, particularly non alcoholic fatty liver disease (NAFLD).
- a DPP-4 inhibitor as defined herein for the manufacture of a pharmaceutical composition for treatment and/or prevention of those diseases given hereinabove or hereinbelow, particularly non alcoholic fatty liver disease (NAFLD).
- the present invention further provides a fixed or non-fixed combination including a kit-of-parts for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD), said combination comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan).
- NAFLD non alcoholic fatty liver disease
- the present invention further provides the use of a DPP-4 inhibitor as defined herein in combination with one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), for the manufacture of a pharmaceutical composition for treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD).
- active substances such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan)
- NAFLD non alcoholic fatty liver disease
- the present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (particularly diabetic NAFLD), said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), such as e.g. for separate, sequential, simultaneous, concurrent or chronologically staggered use of the active ingredients.
- a pharmaceutical composition for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (particularly diabetic NAFLD), said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), such as e.g
- the present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD), said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein as sole active ingredient or, optionally, together with one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), and, optionally, one or more pharmaceutically acceptable carriers and/or diluents.
- NAFLD non alcoholic fatty liver disease
- the present invention further provides a method of treating and/or preventing any of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD), said method comprising administering to a subject in need thereof (particularly a human patient) an effective amount of a DPP-4 inhibitor as defined herein, optionally alone or in combination, such as e.g. separately, sequentially, simultaneously, concurrently or chronologically staggered with an effective amount of one, two or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan).
- NAFLD non alcoholic fatty liver disease
- non alcoholic fatty liver disease within the meaning of this invention includes, without being limited to hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis.
- non alcoholic fatty liver disease within the meaning of this invention refers to non-alcoholic steatohepatitis (NASH).
- the therapies of this invention provide improvements in one or more histopathological features of patients, such as e.g. in portal inflammation, hepatosteatosis, ballooning degeneration, and/or lobular inflammation.
- a DPP-4 inhibitor within the meaning of the present invention include, without being limited to, any of those DPP-4 inhibitors mentioned hereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.
- a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of formula (I)
- R1 denotes ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino, or its pharmaceutically acceptable salt.
- a DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor selected from the group consisting of
- preferred DPP-4 inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts:
- DPP-4 inhibitors are distinguished from structurally comparable DPP-4 inhibitors, as they combine exceptional potency and a long-lasting effect with favourable pharmacological properties, receptor selectivity and a favourable side-effect profile or bring about unexpected therapeutic advantages or improvements when combined with other pharmaceutical active substances.
- Their preparation is disclosed in the publications mentioned.
- a more preferred DPP-4 inhibitor among the abovementioned DPP-4 inhibitors of embodiment A of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, particularly the free base thereof (which is also known as BI 1356).
- preferred DPP-4 inhibitors are selected from the group consisting of saxagliptin and alogliptin, and their pharmaceutically acceptable salts.
- the definitions of the active compounds (including the DPP-4 inhibitors) mentioned hereinabove and hereinbelow also comprise their pharmaceutically acceptable salts as well as hydrates, solvates and polymorphic forms thereof. With respect to salts, hydrates and polymorphic forms thereof, particular reference is made to those which are referred to herein.
- the methods of synthesis for the DPP-4 inhibitors according to embodiment A of this invention are known to the skilled person.
- the DPP-4 inhibitors according to embodiment A of this invention can be prepared using synthetic methods as described in the literature.
- purine derivatives of formula (I) can be obtained as described in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, the disclosures of which are incorporated herein.
- Purine derivatives of formula (II) can be obtained as described, for example, in WO 2004/050658 or WO 2005/110999, the disclosures of which are incorporated herein.
- Purine derivatives of formula (III) and (IV) can be obtained as described, for example, in WO 2006/068163, WO 2007/071738 or WO 2008/017670, the disclosures of which are incorporated herein.
- the preparation of those DPP-4 inhibitors, which are specifically mentioned hereinabove, is disclosed in the publications mentioned in connection therewith.
- Polymorphous crystal modifications and formulations of particular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO 2007/128724, respectively, the disclosures of which are incorporated herein in their entireties.
- Formulations of particular DPP-4 inhibitors with metformin or other combination partners are described in PCT/EP2009053978, the disclosure of which is incorporated herein in its entirety.
- Typical dosage strengths of the dual combination of BI 1356/metformin are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- the compounds of this invention are usually used in dosages from 0.001 to 100 mg/kg body weight, preferably at 0.1-15 mg/kg, in each case 1 to 4 times a day.
- the compounds, optionally combined with other active substances may be incorporated together with one or more inert conventional carriers and/or diluents, e.g.
- compositions according to this invention comprising the DPP-4 inhibitors as defined herein are thus prepared by the skilled person using pharmaceutically acceptable formulation excipients as described in the art.
- excipients include, without being restricted to diluents, binders, carriers, fillers, lubricants, flow promoters, crystallisation retardants, disintegrants, solubilizers, colorants, pH regulators, surfactants and emulsifiers.
- Suitable diluents for compounds according to embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.
- Suitable lubricants for compounds according to embodiment A include talc, polyethyleneglycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
- Suitable binders for compounds according to embodiment A include copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose (L-HPC).
- Suitable disintegrants for compounds according to embodiment A include corn starch or crospovidone.
- the dosage typically required of the DPP-4 inhibitors mentioned herein in embodiment A when administered intravenously is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day.
- 0.1 mg to 10 mg preferably 0.25 mg to 5 mg
- 0.5 mg to 100 mg preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day.
- the dosage of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine when administered orally may be 5 mg to 50 mg, 20 mg to 50 mg, 0.5 mg to 10 mg, or 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.
- a dosage form prepared with a pharmaceutical composition comprising a DPP-4 inhibitor mentioned herein in embodiment A contain the active ingredient in a dosage range of 0.1-100 mg.
- dosage strengths of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.
- a compound of this invention required for use in treatment and/or prevention may vary, e.g. with the nature and stage of the disease or condition being treated and/or prevented.
- the doses of DPP-4 inhibitors mentioned herein in embodiment B to be administered to mammals may be generally from about 0.5 mg to about 350 mg, for example from about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg, of the active moiety per person per day, or from about 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size.
- Single dosage strengths comprise, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.
- a dosage strength of the DPP-4 inhibitor sitagliptin is usually between 25 and 200 mg of the active moiety.
- a recommended dose of sitagliptin is 100 mg calculated for the active moiety (free base anhydrate) once daily.
- Unit dosage strengths of sitagliptin free base anhydrate (active moiety) are 25, 50, 75, 100, 150 and 200 mg.
- Particular unit dosage strengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg.
- An equivalent amount of sitagliptin phosphate monohydrate to the sitagliptin free base anhydrate is used in the pharmaceutical compositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg, respectively.
- Adjusted dosages of 25 and 50 mg sitagliptin are used for patients with renal failure.
- Typical dosage strengths of the dual combination of sitagliptin/metformin are 50/500 mg and 50/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- a dosage range of the DPP-4 inhibitor vildagliptin is usually between 10 and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or 25 and 50 mg or 50 and 100 mg daily.
- Particular examples of daily oral dosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg.
- the daily administration of vildagliptin may be between 25 and 150 mg or between 50 and 100 mg.
- the daily administration of vildagliptin may be 50 or 100 mg.
- the application of the active ingredient may occur up to three times a day, preferably one or two times a day.
- Particular dosage strengths are 50 mg or 100 mg vildagliptin.
- Typical dosage strengths of the dual combination of vildagliptin/metformin are 50/850 mg and 50/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- Alogliptin may be administered to a patient at a daily dose of between 5 mg/day and 250 mg/day, optionally between 10 mg and 200 mg, optionally between 10 mg and 150 mg, and optionally between 10 mg and 100 mg of alogliptin (in each instance based on the molecular weight of the free base form of alogliptin).
- specific dosage amounts that may be used include, but are not limited to 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of alogliptin per day.
- Alogliptin may be administered in its free base form or as a pharmaceutically acceptable salt.
- Saxagliptin may be administered to a patient at a daily dose of between 2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg.
- Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg of saxagliptin per day.
- Typical dosage strengths of the dual combination of saxagliptin/metformin are 2.5/500 mg and 2.5/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- DPP-4 inhibitors of this invention refers to those orally administered DPP-4 inhibitors which are therapeutically efficacious at low dose levels, e.g. at oral dose levels ⁇ 100 mg or ⁇ 70 mg per patient per day, preferably ⁇ 50 mg, more preferably ⁇ 30 mg or ⁇ 20 mg, even more preferably from 1 mg to 10 mg, particularly from 1 mg to 5 mg (more particularly 5 mg), per patient per day (if required, divided into 1 to 4 single doses, particularly 1 or 2 single doses, which may be of the same size, preferentially, administered orally once- or twice daily (more preferentially once-daily), advantageously, administered at any time of day, with or without food.
- the daily oral amount 5 mg BI 1356 can be given in a once daily dosing regimen (i.e. 5 mg BI 1356 once daily) or in a twice daily dosing regimen (i.e. 2.5 mg BI 1356 twice daily), at any time of day, with or without food.
- a particularly preferred DPP-4 inhibitor to be emphasized within the meaning of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (also known as BI 1356).
- BI 1356 exhibits high potency, 24 h duration of action, and a wide therapeutic window. In people with type 2 diabetes BI 1356 shows a placebo-like safety and tolerability. With low doses of about ⁇ 5 mg, BI 1356 acts as a true once-daily oral drug with a full 24 h duration of DPP-4 inhibition.
- BI 1356 is mainly excreted via the liver and only to a minor extent (about ⁇ 7% of the administered oral dose) via the kidney. BI 1356 is primarily excreted unchanged via the bile. The fraction of BI 1356 eliminated via the kidneys increases only very slightly over time and with increasing dose, so that there will likely be no need to modify the dose of BI 1356 based on the patients' renal function. The non-renal elimination of BI 1356 in combination with its low accumulation potential and broad safety margin may be of significant benefit in a diabetes patient population that has a high prevalence of renal insufficiency and diabetic nephropathy.
- a DPP-4 inhibitor is combined with active substances customary for the respective disorders, such as e.g. one or more active substances selected from among the other antidiabetic substances, especially active substances that lower the blood sugar level or the lipid level in the blood, raise the HDL level in the blood, lower blood pressure or are indicated in the treatment of atherosclerosis or obesity.
- active substances customary for the respective disorders such as e.g. one or more active substances selected from among the other antidiabetic substances, especially active substances that lower the blood sugar level or the lipid level in the blood, raise the HDL level in the blood, lower blood pressure or are indicated in the treatment of atherosclerosis or obesity.
- a DPP-4 inhibitor may be combined with one or more antioxidants and/or anti-inflammatory agents.
- a DPP-4 inhibitor may be combined with one or more vascular endothelial protective agents.
- Such a combined treatment may be given as a free combination of the substances or in the form of a fixed combination, for example in a tablet or capsule.
- Pharmaceutical formulations of the combination partner(s) needed for this may either be obtained commercially as pharmaceutical compositions or may be formulated by the skilled man using conventional methods.
- the active substances which may be obtained commercially as pharmaceutical compositions are described in numerous places in the prior art, for example in the list of drugs that appears annually, the “Rote Liste®” of the federal association of the pharmaceutical industry, or in the annually updated compilation of manufacturers' information on prescription drugs known as the “Physicians' Desk Reference”.
- Examples of antidiabetic combination partners are metformin; sulphonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidon, glibornuride and gliclazide; nateglinide; repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone; PPAR gamma modulators such as metaglidases; PPAR-gamma agonists such as GI 262570; PPAR-gamma antagonists; PPAR-gamma/alpha modulators such as tesaglitazar, muraglitazar and KRP297; PPAR-gamma/alpha/delta modulators; AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT)
- exenatide exenatide LAR, liraglutide, taspoglutide or albiglutide
- SGLT2-inhibitors such as KGT-1251; inhibitors of protein tyrosine-phosphatase; inhibitors of glucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvate dehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf.
- PEPCK phosphoenolpyruvatecarboxykinase
- PDK pyruvate dehydrogenasekinase
- inhibitors of tyrosine-kinases 50 mg to 600 mg
- a preferred example of an antidiabetic combination partner is metformin, which is usually given in doses varying from about 250 mg to 3000 mg, particularly from 500 mg to 2000 mg up to 2500 mg per day using various dosing regimens, such as e.g. usually in doses of about 100 mg to 500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mg once or twice a day, or delayed-release metformin in doses of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg once a day.
- Particular dosage strengths may be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.
- pioglitazone usually in a dosage of about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day.
- Rosiglitazone is usually given in doses from 4 to 8 mg once (or divided twice) a day (typical dosage strengths are 2, 4 and 8 mg).
- Glibenclamide is usually given in doses from 2.5-5 to 20 mg once (or divided twice) a day (typical dosage strengths are 1.25, 2.5 and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mg once (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5 and 6 mg).
- Glipizide is usually given in doses from 2.5 to 10-20 mg once (up to 40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg), or extended-release glipizide in doses from 5 to 10 mg (up to 20 mg) once a day (typical dosage strengths are 2.5, 5 and 10 mg).
- Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) once a day (typical dosage strengths are 1, 2 and 4 mg).
- a dual combination of glibenclamide/metformin is usually given in doses from 1.25/250 once daily to 10/1000 mg twice daily (typical dosage strengths are 1.25/250, 2.5/500 and 5/500 mg).
- a dual combination of glipizide/metformin is usually given in doses from 2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250, 2.5/500 and 5/500 mg).
- a dual combination of glimepiride/metformin is usually given in doses from 1/250 to 4/1000 mg twice daily.
- a dual combination of rosiglitazone/glimepiride is usually given in doses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosage strengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg).
- a dual combination of pioglitazone/glimepiride is usually given in doses from 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and 45/4 mg).
- a dual combination of rosiglitazone/metformin is usually given in doses from 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg).
- a dual combination of pioglitazone/metformin is usually given in doses from 15/500 once or twice daily to 15/850 mg thrice daily (typical dosage strengths are 15/500 and 15/850 mg).
- the non-sulphonylurea insulin secretagogue nateglinide is usually given in doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosage strengths are 60 and 120 mg); repaglinide is usually given in doses from 0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are 0.5, 1 and 2 mg).
- a dual combination of repaglinide/metformin is available in dosage strengths of 1/500 and 2/850 mg.
- Acarbose is usually given in doses from 25 to 100 mg with meals (up to 300 mg/day, typical dosage strengths are 25, 50 and 100 mg).
- Miglitol is usually given in doses from 25 to 100 mg with meals (up to 300 mg/day, typical dosage strengths are 25, 50 and 100 mg).
- HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etofyllinclofibrate; nicotinic acid and the derivatives thereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC 2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such as ezetimib; substances that bind to bile acid, such as cholestyramine, colestipol and colesevelam; inhibitors of bile acid transport; HDL modul
- a dosage of the partner drug atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mg once a day
- beta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol and carvedilol
- diuretics such as hydrochlorothiazide, chlortalidon, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene
- calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem
- ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, ben
- a dosage of the partner drug telmisartan is usually from 20 mg to 320 mg or 40 mg to 160 mg per day.
- combination partners which increase the HDL level in the blood are Cholesteryl Ester Transfer Protein (CETP) inhibitors; inhibitors of endothelial lipase; regulators of ABC1; LXRalpha antagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/beta regulators, and substances that increase the expression and/or plasma concentration of apolipoprotein A-I.
- CETP Cholesteryl Ester Transfer Protein
- combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme; dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as the CB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 as well as NPY2 antagonists; beta3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such as APD 356; myostatin inhibitors; Acrp30 and adiponectin; steroyl CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; and tesofensine.
- sibutramine tetrahydrolipstatin (orlistat); alizyme; dexfenfluramine; axok
- combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.
- phospholipase A2 inhibitors inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano; ASA
- antioxidant combination partners are selenium, betaine, vitamin C, vitamin E and beta carotene.
- an anti-inflammatory combination partner is pentoxifylline; another example of an anti-inflammatory combination partner is a PDE-4 inhibitor, such as e.g. tetomilast, roflumilast, or 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid (or other species disclosed in U.S. Pat. No. 7,153,854, WO 2004/063197, U.S. Pat. No. 7,459,451 and/or WO 2006/004188).
- PDE-4 inhibitor such as e.g. tetomilast, roflumilast, or 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid (or other species disclosed in U.S. Pat. No
- an anti-inflammatory partner drug is a caspase inhibitor, such as e.g. (3S)-5-fluoro-3-( ⁇ [(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl ⁇ amino-4-oxopentanoic acid (or other species disclosed in WO 2005/021516 and/or WO 2006/090997).
- a caspase inhibitor such as e.g. (3S)-5-fluoro-3-( ⁇ [(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl ⁇ amino-4-oxopentanoic acid (or other species disclosed in WO 2005/021516 and/or WO 2006/090997).
- vascular endothelial protective agent is a PDE-5 inhibitor, such as e.g. sildenafil, vardenafil or tadalafil; another example of a vascular endothelial protective agent is a nitric oxide donor.
- a DPP-4 inhibitor may be combined with one or more CCK-2 or gastrin agonists, such as e.g. proton pump inhibitors (including reversible as well as irreversible inhibitors of the gastric H+/K+-ATPase), for example omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.
- CCK-2 or gastrin agonists such as e.g. proton pump inhibitors (including reversible as well as irreversible inhibitors of the gastric H+/K+-ATPase), for example omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.
- DPP-4 inhibitor to be emphasized within the meaning of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base (also known as BI 1356).
- mice Female db/db mice [C57BLKS/Bom-db/db; Charles-River, Germany], aged 6-7 weeks at start are treated 8 weeks with the DPP-4 inhibitor. Animals are kept in groups of 5-6 mice in Makrolon® cages with free access to food and tap water. The room is maintained as follows: dark light rhythm [6 a.m. to 6 p.m. light], room temperature 22 ⁇ 2° C., relative humidity 50 ⁇ 10%.
- the DPP-4 inhibitor is suspended in 0.5% [w/v] natrosol.
- Single daily oral administrations of 3 mg/kg/d of the DPP-4 inhibitor in a volume of 5 ml/kg by gavage are performed.
- Control animals receive 0.5% [w/v] natrosol, also in a volume of 5 ml/kg.
- At the end of the treatment period [8 weeks after treatment start] animals are dissected and liver biopsies taken.
- MCD induced steatosis Male C57BL/6 mice [C57BL/6NC] supplied by Charles River, Germany] are allowed to normal diet or a MCD (methionine and cholin deficient diet) (Research Diets, New Brunswick, USA) and tap water ad libitum throughout the experimental period. At first, all mice are fed the normal diet during a 1-week quarantine and acclimation period.
- mice displaying no abnormal findings at the end of the quarantine and acclimation period are randomly divided into groups (8-10 mice/group) and are treated for 5 weeks as follows: group 1 (normal), fed normal diet plus vehicle (0.5% [w/v] natrosol); group 2 (MCD control), fed MCD diet plus vehicle; group 3, fed MCD diet plus the DPP-4 inhibitor (3 mg/kg/day).
- group 1 normal
- group 2 MCD control
- group 3 fed MCD diet plus the DPP-4 inhibitor (3 mg/kg/day).
- blood samples are collected from the tail vein of the mice and the livers are collected. Histological analysis of inflammation and fibrosis are performed like under necropsy and histology.
- Samples for hepatic triglycerides measurement are generated by homogenizing a liver lobe in lysis buffer (0.5% polyoxyethylen 10 tridecylether (Sigma, P 2393), 0.01 M NaPi, 1 mM EDTA, pH 7.4). The liver tissue is previously heated in the same buffer 10 min to 95° C. Following the initial homogenization, samples are further processed using the MP Biotech (FastPrep-24) equipment and orange caps (2 ⁇ 45 s). Samples are then centrifuged 2 min at 3000 rpm. The supernatant is collected for further analysis. Triglyceride content is measured using the Sigma serum triglyceride kit (Sigma, TR 0100).
- Necropsy is performed in ad libitum fed animals. Animals are anesthetized with 3% isoflurane/oxygen [Isoba®, batch J10417, Essex Pharma GmbH, 81737, Germany]. The liver is removed and fixed in 4% paraformaldhyd solution for later microscopic. Liver lipidosis is evaluated blinded and semi-quantitatively by light microscopy. The slides are blindly examinated on coded slides and all parameters (e.g. steatosis, inflammation) are semi-quantitatively scored (severity index) by the following scheme:
- Score 1 no changes
- Score 2 minimal changes ( ⁇ 5% of liver tissues affected)
- Score 3 mild changes (5-15% of liver tissue affected)
- Score 4 moderate changes (15-25% of liver tissue affected)
- Score 5 severe changes (>25% of liver tissue affected)
- C57BL/6 mice with diet-induced steatosis are anesthetised by continuous inhalation of 2% isoflurane in a N 2 O:O 2 , (70:30, v:v) gas mixture.
- NMR measurements are performed on a Bruker BioSpec 47/40 scanner (Bruker BioSpin, Ettlingen, Germany) equipped with a BGA12 gradient coil system. A volume coil is used for excitation, a surface coil for signal reception.
- a pilot scan comprising horizontal and axial MR images is acquired using a gradient-echo pulse sequence with the following parameters: TR 135 ms, TE 3.5 ms, field-of view 45 ⁇ 45 mm 2 , matrix 128 2 , slice thickness 1.75 mm.
- a voxel-of-interest (VOI, 3 ⁇ 3 ⁇ 3 mm 3 ) is placed in the left ventral part of the liver. Liver lipids in the VOI are measured by NMR spectroscopy using a PRESS sequence (point-resolved spectroscopy) with the following parameters: TR 1050 ms, TE 20 ms, number of averages 32, digital resolution 1024 data points. Data are analyzed using the commercially available software package LCModel by S. W. Provencher.
- FIG. 1 DIO mice 2 months on high fat diet (liver fat day 29 following treatment/control): FIG. 1
- FIG. 2 DIO mice 4 months on high fat diet (liver fat day 21 following treatment/control): FIG. 2
- the effect on fatty liver diseases of the DPP-4 inhibitors of this invention can be tested in the models given herein and/or studied and detected by the methods described hereinabove and hereinbelow.
- the effect on various forms of fibrosis can be studied via the following detection methods:
- RNA is isolated using a RNeasy Mini-kit (Qiagen, Germany). Transcripts for collagen type I, TGF- ⁇ 1, procollagen ⁇ 1(I), TIMP-1 (tissue inhibitor of matrix metalloproteinases-1), metalloproteases 1, 2, 3, 8, 9, 13 (MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-13), PDGF- ⁇ receptor and ⁇ -smooth muscle cell actin are analysed via TQ-PCR and normalized to GAPDH mRNA.
- Sections 5 ⁇ m thick from formalin fixed, paraffin embedded tissue are prepared and are stained with Sirius red (saturated picric acid in distillated water containing 0.1% (w/v) Sirius red F3B (BDH Chemicals, UK) to allow visualisation of liver fibrosis. All samples from a series of experiments are stained simultaneously and evaluated in a blinded fashion.
- Sirius red saturated picric acid in distillated water containing 0.1% (w/v) Sirius red F3B (BDH Chemicals, UK
- Necropsy is performed in ad libitum fed animals. Animals are anesthetized with 3% isoflurane/oxygen [Isoba®, batch J10417, Essex Pharma GmbH, 81737, Germany]. The organs (liver, kidney, lung, etc.) are removed and fixed in 4% paraformaldhyd solution for later microscopic. Fibrosis is evaluated blinded and semi-quantitatively by light microscopy. The slides are blindly examinated on coded slides and all parameters are semi-quantitatively scored (severity index) by the following scheme 1 : 1 ) Ishak etal. J Hepatol 22: 696, 1995
- Fibrosis is associated with increased stiffness and viscosity of the tissue.
- the viscoelastic properties of living tissue can be assessed with Magnetic Resonance Elastography (MRE) by measuring the propagation of low-frequency mechanical shear waves through the tissue. The propagation of the shear waves is visualized by non-invasive Magnetic Resonance Imaging (MRI), from which parameters for the mechanical properties of the tissue can be derived.
- MRE Magnetic Resonance Elastography
- MRI Magnetic Resonance Imaging
Abstract
The present invention relates to the finding that certain DPP-4 inhibitors are particularly suitable for treating and/or preventing non alcoholic fatty liver diseases (NAFLD).
Description
- The present invention relates to certain DPP-4 inhibitors for treating and/or preventing non alcoholic fatty liver diseases (NAFLD) and to the use of these DPP-4 inhibitors in treating and/or preventing NAFLD and/or diseases related or associated therewith. The invention also relates to combinations of certain DPP-4 inhibitors with other active substances for treating and/or preventing NAFLD and to the use of combinations of these DPP-4 inhibitors with other active substances for treating and/or preventing NAFLD. Pharmaceutical compositions for use in the treatment and/or prevention of non alcoholic fatty liver diseases (NAFLD) comprising a DPP-4 inhibitor as defined herein optionally together with one or more other active substances are also contemplated.
- The spectrum of fatty liver diseases associated with metabolic determinants and not resulting from alcohol (NAFLD, non-alcoholic fatty liver diseases) extends from simple hepatic steatosis through inflammatory steatohepatitis (NASH, non-alcoholic steatohepatitis) to liver fibrosis and cirrhosis, as well as, in some cases, hepatocellular carcinomas. NASH is the most severe form of NAFLD and recent data indicate prevalences for NASH and NAFLD in the range of 17-33% (in US). Thus, NASH and NAFLD have emerged as clinically important types of chronic liver diseases in industrialized countries (McCullough 2006). The underlying pathophysiological mechanisms of NAFLD and NASH are currently tried to be explained by the first and second hit theory. As a primary event hepatic steatosis is emerging due to either extra-hepatic (e.g. increased free fatty acid influx, insulin resistance, fasting, low levels of adiponectin) or intra-hepatic (e.g. decreased capacity to secrete VLDL, decreased β-oxidation) disturbances. The first hit leads to hepatic steatosis and predisposes and triggers the second hit for an inflammatory event. In this context, increased levels of reactive oxygen species (ROS) and elevated levels of pro-inflammatory cytokines like TNF-a are discussed to promote inflammation. A significant role for the development of NASH and NAFLD accords to the insulin resistance of obese and diabetic individuals. Thus, current therapies focus on break through strategies of insulin resistance by the mean of insulin sensitizers like TZD (thiazolidinediones) or metformin. There are some encouraging results from clinical pilot studies using pioglitazone (Promat 2004) of rosiglitazone (Neuschwander 2003) as well as metformin (Zhou 2001). However, TZD therapy is associated with massive weight gain and fat redistribution. In addition, TZD cause fluid retention and are not indicated in patients with congestive heart failure. Long term treatment with TZD are further associated with an increased risk of bone fractures. Other therapeutic approaches to NASH and NAFLD are rather conservative comprising diet and exercise and weight control. Further, NAFLD and particularly NASH is also associated with an increased risk for endothelial dysfunction and cardiovascular risk, especially over long term. Thus, there is still a high unmet need and a high demand of novel and efficacious medicaments for the treatment of NAFLD and NASH. In a recent publication in the Annals of Hepatology (2007) Balaban et al. focused on the role of DPP-4 expression in NASH patients and correlated DPP-4 intensity of immunostaining with histopathological grade of hepatosteatosis and thus, providing additional evidence for the use of DPP-4 inhibitors in this indication.
- The enzyme DPP-4 also known as CD26 is a serine protease known to lead to the cleavage of a dipeptide from the N-terminal end of a number of proteins having at their N-terminal end a prolin or alanin residue. Due to this property DPP-4 inhibitors interfere with the plasma level of bioactive peptides including the peptide GLP-1 and are considered to be promising drugs for the treatment of diabetes mellitus.
- For example, DPP-4 inhibitors and their uses are disclosed in WO 2002/068420, WO 2004/018467, WO 2004/018468, WO 2004/018469, WO 2004/041820, WO 2004/046148, WO 2005/051950, WO 2005/082906, WO 2005/063750, WO 2005/085246, WO 2006/027204, WO 2006/029769 or WO2007/014886; or in WO 2004/050658, WO 2004/111051, WO 2005/058901 or WO 2005/097798; or in WO 2006/068163, WO 2007/071738 or WO 2008/017670; or in WO 2007/128721 or WO 2007/128761.
- As further DPP-4 inhibitors the following compounds can be mentioned:
- Sitagliptin (MK-0431) having the structural formula A below is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-5H[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, also named (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine,
- In one embodiment, sitagliptin is in the form of its dihydrogenphosphate salt, i.e. sitagliptin phosphate. In a further embodiment, sitagliptin phosphate is in the form of a crystalline anhydrate or monohydrate. A class of this embodiment refers to sitagliptin phosphate monohydrate. Sitagliptin free base and pharmaceutically acceptable salts thereof are disclosed in U.S. Pat. No. 6,699,871 and in Example 7 of WO 03/004498. Crystalline sitagliptin phosphate monohydrate is disclosed in WO 2005/003135 and in WO 2007/050485.
For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents. - A tablet formulation for sitagliptin is commercially available under the trade name Januvia®. A tablet formulation for sitagliptin/metformin combination is commercially available under the trade name Janumet®.
- Vildagliptin (LAF-237) having the structural formula B below is (2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile, also named (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyano-pyrrolidine,
- Vildagliptin is specifically disclosed in U.S. Pat. No. 6,166,063 and in Example 1 of WO 00/34241. Specific salts of vildagliptin are disclosed in WO 2007/019255. A crystalline form of vildagliptin as well as a vildagliptin tablet formulation are disclosed in WO 2006/078593. Vildagliptin can be formulated as described in WO 00/34241 or in WO 2005/067976. A modified release vildagliptin formulation is described in WO 2006/135723.
For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents. - A tablet formulation for vildagliptin is commercially available under the trade name Galvus®. A tablet formulation for vildagliptin/metformin combination is commercially available under the trade name Eucreas®.
- Saxagliptin (BMS-477118) having the structural formula C below is (1S,3S,5S)-2-{(2S)-2-amino-2-(3-hydroxyadamantan-1-yl)acetyl}-2-azabicyclo[3.1.0]hexane-3-carbonitrile, also named (S)-3-hydroxyadamantylglycine-L-cis-4,5-methanoprolinenitrile,
- Saxagliptin is specifically disclosed in U.S. Pat. No. 6,395,767 and in Example 60 of WO 01/68603.
In one embodiment, saxagliptin is in the form of its HCl salt or its mono-benzoate salt as disclosed in WO 2004/052850. In a further embodiment, saxagliptin is in the form of the free base. In a yet further embodiment, saxagliptin is in the form of the monohydrate of the free base as disclosed in WO 2004/052850. Crystalline forms of the HCl salt and the free base of saxagliptin are disclosed in WO 2008/131149. A process for preparing saxagliptin is also disclosed in WO 2005/106011 and WO 2005/115982. Saxagliptin can be formulated in a tablet as described in WO 2005/117841.
For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents. - Alogliptin (SYR-322) having the structural formula E below is 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl}methyl)benzonitrile
- Alogliptin is specifically disclosed in US 2005/261271, EP 1586571 and in WO 2005/095381. In one embodiment, alogliptin is in the form of its benzoate salt, its hydrochloride salt or its tosylate salt each as disclosed in WO 2007/035629. A class of this embodiment refers to alogliptin benzoate. Polymorphs of alogliptin benzoate are disclosed in WO 2007/035372. A process for preparing alogliptin is disclosed in WO 2007/112368 and, specifically, in WO 2007/035629. Alogliptin (namely its benzoate salt) can be formulated in a tablet and administered as described in WO 2007/033266. Formulations of Aloglipitin with metformin or pioglitazone are described in WO 2008/093882 or WO 2009/011451, respectively.
For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents. - (2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof, preferably the mesylate, or (2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof.
- These compounds and methods for their preparation are disclosed in WO 03/037327. The mesylate salt of the former compound as well as crystalline polymorphs thereof are disclosed in WO 2006/100181. The fumarate salt of the latter compound as well as crystalline polymorphs thereof are disclosed in WO 2007/071576. These compounds can be formulated in a pharmaceutical composition as described in WO 2007/017423.
- For details, e.g. on a process to manufacture, to formulate or to use these compounds or salts thereof, reference is thus made to these documents.
- (S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one or a pharmaceutically acceptable salt thereof:
- This compound and methods for its preparation are disclosed in WO 2005/000848. A process for preparing this compound (specifically its dihydrochloride salt) is also disclosed in WO 2008/031749, WO 2008/031750 and WO2008/055814. This compound can be formulated in a pharmaceutical composition as described in WO 2007/017423.
For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents. - (3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone or a pharmaceutically acceptable salt thereof.
- This compound and methods for its preparation are disclosed in WO 2005/116014 and U.S. Pat. No. 7,291,618.
- For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- (1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one or a pharmaceutically acceptable salt thereof:
- This compound and methods for its preparation are disclosed in WO 2007/148185 and US 20070299076. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- (2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile or a pharmaceutically acceptable salt thereof:
- This compound and methods for its preparation are disclosed in WO 2006/040625 and WO 2008/001195. Specifically claimed salts include the methanesulfonate and p-toluenesulfonate. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- (R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile or a pharmaceutically acceptable salt thereof:
- This compound and methods for its preparation and use are disclosed in WO 2005/095381, US 2007060530, WO 2007/033350, WO 2007/035629, WO 2007/074884, WO 2007/112368 and WO 2008/033851. Specifically claimed salts include the succinate (WO 2008/067465), benzoate, benzenesulfonate, p-toluenesulfonate, (R)-mandelate and hydrochloride. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- 5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide or a pharmaceutically acceptable salt thereof:
- This compound and methods for its preparation are disclosed in WO 2006/116157 and US 2006/270701. For details, e.g. on a process to manufacture, to formulate or to use this compound or a salt thereof, reference is thus made to these documents.
- For avoidance of any doubt, the disclosure of each of the foregoing documents cited above is specifically incorporated herein by reference in its entirety.
- Within the scope of the present invention it has now surprisingly been found that DPP-4 inhibitors as defined herein have surprising and particularly advantageous properties, which make them particularly suitable for treating and/or preventing (including preventing, slowing, delaying and/or reversing the progression or reducing the occurrence or delaying the onset) of non alcoholic fatty liver disease (NAFLD) including hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis, and/or diseases related therewith (such as e.g. diabetes, insulin insensitivity, hepatic glucose overproduction and/or metabolic syndrome) or associated therewith (such as e.g. cardiovascular disease and/or atherosclerosis or other (cardio)metabolic disorders), and thus for preventing liver cirrhosis (irreversible advanced scarring of the liver) and/or hepatocellular carcinomas.
- Thus, the present invention provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of non alcoholic fatty liver disease (NAFLD).
- In addition, the present invention further provides a DPP-4 inhibitor as defined herein for use in improving insulin sensitivity.
- The present invention further provides a DPP-4 inhibitor as defined herein for use in decreasing glucose production in the liver.
- The present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of insulin resistance and/or insulin resistance syndrome.
- The present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of metabolic syndrome.
- The present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of one or more of the features associated with the metabolic syndrome, such as e.g. NAFLD/NASH, (central) obesity, diabetes, dyslipidemia, hypertension and/or atherosclerotic (cardio)vascular disease or damages.
- The present invention further provides a DPP-4 inhibitor as defined herein for use in preventing and/or reducing the risk of adverse effects associated with existing therapies of NAFLD/NASH (e.g. using TZD and/or metformin).
- Further, the present invention further provides a DPP-4 inhibitor as defined herein for reducing the risk of endothelial dysfunction and/or cardiovascular disease or events, e.g. while treating NAFLD/NASH.
- Also, the present invention provides a DPP-4 inhibitor as defined herein for reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight or positively influencing body fat distribution.
- The present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of obesity, especially of severe or extreme obesity (e.g. class II or III), e.g. with a BMI ≧35 or even ≧40 kg/m2 (or ≧30 kg/m2 for Japanese patients), particularly abdominal and/or visceral obesity.
- The present invention further provides a DPP-4 inhibitor as defined herein for treating and/or preventing (including reducing the risk of developing or progressing) NAFLD/NASH and/or diseases or disorders related or associated therewith, particularly in patients with or at risk of NAFLD/NASH, such as e.g. those patients having one or more disorders selected from NAFLD, metabolic syndrome, insulin resistance, IGT, IFG, overweight, obesity (e.g. BMI ≧25-30 kg/m2, waist circumference >88 (women)—102 (men) cm, and/or waist:hip ratio >0.85 (women)—0.9 (men), particularly visceral and/or abdominal obesity), dyslipidemia (including hyperlipidemia, particularly hypertriglyceridemia (e.g. blood triglyceride level ≧150 mg/dL) and/or hypoHDLemia (e.g. blood HDL cholesterol level <40 (men)—50 (women) mg/dL), diabetes (particularly
type 2 diabetes), hypertension (e.g. ≧130/≧85 mmHg), hyperglycemia, hyperinsulinemia, hyperuricemia, severe sleep apnoe, polycystic ovary syndrome, and chronic hepatitis C infection; particularly including elderly patients >45 years. - The present invention further provides a DPP-4 inhibitor as defined herein for treating and/or preventing (including reducing the risk of developing or progressing) metabolic disorders or diseases, especially diabetes (particularly
type 2 diabetes), in patients having NAFLD/NASH. - Further, according to another aspect of the invention, there is provided the use of a DPP-4 inhibitor as defined herein for the manufacture of a medicament for one or more of the following purposes:
-
- preventing, slowing the progression of, delaying or treating a metabolic disorder or disease, such as e.g. type 1 diabetes mellitus,
type 2 diabetes mellitus, impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), hyperglycemia, postprandial hyperglycemia, overweight, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertension, atherosclerosis, endothelial dysfunction, osteoporosis, chronic systemic inflammation, retinopathy, neuropathy, nephropathy and/or metabolic syndrome; - improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c;
- preventing, slowing, delaying or reversing progression from impaired glucose tolerance (IGT), impaired fasting blood glucose (IFG), insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus;
- preventing, reducing the risk of, slowing the progression of, delaying or treating of complications of diabetes mellitus such as micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, cardio- or cerebrovascular diseases, tissue ischaemia, diabetic foot or ulcus, atherosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders, vascular restenosis, and/or stroke;
- reducing body weight or preventing an increase in body weight or facilitating a reduction in body weight;
- preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the functionality of pancreatic beta cells and/or stimulating and/or restoring the functionality of pancreatic insulin secretion;
- for reducing the risk for adverse effects associated with conventional (oral) antihyperglycemic medication; and/or
- maintaining and/or improving the insulin sensitivity and/or for treating or preventing hyperinsulinemia and/or insulin resistance;
particularly in a patient having NAFLD, optionally in combination with one or more other active substances, such as e.g. any of those mentioned herein.
- preventing, slowing the progression of, delaying or treating a metabolic disorder or disease, such as e.g. type 1 diabetes mellitus,
- In addition, the present invention further provides a DPP-4 inhibitor as defined herein for use in the treatment and/or prevention of fibrosis, such as e.g. fibrosis of the liver, lung, skin, heart or kidney.
- The present invention further provides the use of a DPP-4 inhibitor as defined herein for the manufacture of a pharmaceutical composition for treatment and/or prevention of those diseases given hereinabove or hereinbelow, particularly non alcoholic fatty liver disease (NAFLD).
- The present invention further provides a fixed or non-fixed combination including a kit-of-parts for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD), said combination comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan).
- The present invention further provides the use of a DPP-4 inhibitor as defined herein in combination with one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), for the manufacture of a pharmaceutical composition for treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD).
- The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (particularly diabetic NAFLD), said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein and optionally one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), such as e.g. for separate, sequential, simultaneous, concurrent or chronologically staggered use of the active ingredients.
- The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD), said pharmaceutical composition comprising a DPP-4 inhibitor as defined herein as sole active ingredient or, optionally, together with one or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan), and, optionally, one or more pharmaceutically acceptable carriers and/or diluents.
- The present invention further provides a method of treating and/or preventing any of those diseases given hereinabove, particularly non alcoholic fatty liver disease (NAFLD), said method comprising administering to a subject in need thereof (particularly a human patient) an effective amount of a DPP-4 inhibitor as defined herein, optionally alone or in combination, such as e.g. separately, sequentially, simultaneously, concurrently or chronologically staggered with an effective amount of one, two or more other active substances, such as e.g. any of those mentioned herein, particularly metformin or pioglitazone or an ARB (such as e.g. telmisartan).
- In an embodiment of this invention, non alcoholic fatty liver disease (NAFLD) within the meaning of this invention includes, without being limited to hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis.
- In a special embodiment of this invention, non alcoholic fatty liver disease (NAFLD) within the meaning of this invention refers to non-alcoholic steatohepatitis (NASH).
- In an embodiment of this invention, the therapies of this invention provide improvements in one or more histopathological features of patients, such as e.g. in portal inflammation, hepatosteatosis, ballooning degeneration, and/or lobular inflammation.
- A DPP-4 inhibitor within the meaning of the present invention include, without being limited to, any of those DPP-4 inhibitors mentioned hereinabove and hereinbelow, preferably orally active DPP-4 inhibitors.
- In a first embodiment (embodiment A), a DPP-4 inhibitor in the context of the present invention is any DPP-4 inhibitor of formula (I)
- or formula (II)
- or formula (III)
- or formula (IV)
- wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino,
or its pharmaceutically acceptable salt. - In a second embodiment (embodiment B), a DPP-4 inhibitor in the context of the present invention is a DPP-4 inhibitor selected from the group consisting of
- sitagliptin, vildagliptin, saxagliptin, alogliptin,
(2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,
(3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,
(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,
(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]acetyl}-4-fluoropyrrolidine-2-carbonitrile,
(R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, and
5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide,
or its pharmaceutically acceptable salt. - Regarding the first embodiment (embodiment A), preferred DPP-4 inhibitors are any or all of the following compounds and their pharmaceutically acceptable salts:
-
- 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example 2(142)):
-
- 1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example 2(252)):
-
- 1-[(Quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2004/018468, example 2(80)):
-
- 2-((R)-3-Amino-piperidin-1-yl)-3-(but-2-yinyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (compare WO 2004/050658, example 136):
-
- 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyin-1-yl)-8-[(2-amino-2-methyl-propyl)-methylamino]-xanthine (compare WO 2006/029769, example 2(1)):
-
- 1-[(3-Cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(30)):
-
- 1-(2-Cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(39)):
-
- 1-[(4-Methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine (compare WO 2006/029769, example 2(4)):
-
- 1-[(3-Cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(52)):
-
- 1-[(4-Methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(81)):
-
- 1-[(4,6-Dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(82)):
-
- 1-[(Quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine (compare WO 2005/085246, example 1(83)):
- These DPP-4 inhibitors are distinguished from structurally comparable DPP-4 inhibitors, as they combine exceptional potency and a long-lasting effect with favourable pharmacological properties, receptor selectivity and a favourable side-effect profile or bring about unexpected therapeutic advantages or improvements when combined with other pharmaceutical active substances. Their preparation is disclosed in the publications mentioned.
- A more preferred DPP-4 inhibitor among the abovementioned DPP-4 inhibitors of embodiment A of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, particularly the free base thereof (which is also known as BI 1356).
- Regarding the second embodiment (embodiment B), preferred DPP-4 inhibitors are selected from the group consisting of saxagliptin and alogliptin, and their pharmaceutically acceptable salts.
- Unless otherwise noted, according to this invention it is to be understood that the definitions of the active compounds (including the DPP-4 inhibitors) mentioned hereinabove and hereinbelow also comprise their pharmaceutically acceptable salts as well as hydrates, solvates and polymorphic forms thereof. With respect to salts, hydrates and polymorphic forms thereof, particular reference is made to those which are referred to herein.
- With respect to embodiment A, the methods of synthesis for the DPP-4 inhibitors according to embodiment A of this invention are known to the skilled person. Advantageously, the DPP-4 inhibitors according to embodiment A of this invention can be prepared using synthetic methods as described in the literature. Thus, for example, purine derivatives of formula (I) can be obtained as described in WO 2002/068420, WO 2004/018468, WO 2005/085246, WO 2006/029769 or WO 2006/048427, the disclosures of which are incorporated herein. Purine derivatives of formula (II) can be obtained as described, for example, in WO 2004/050658 or WO 2005/110999, the disclosures of which are incorporated herein. Purine derivatives of formula (III) and (IV) can be obtained as described, for example, in WO 2006/068163, WO 2007/071738 or WO 2008/017670, the disclosures of which are incorporated herein. The preparation of those DPP-4 inhibitors, which are specifically mentioned hereinabove, is disclosed in the publications mentioned in connection therewith. Polymorphous crystal modifications and formulations of particular DPP-4 inhibitors are disclosed in WO 2007/128721 and WO 2007/128724, respectively, the disclosures of which are incorporated herein in their entireties. Formulations of particular DPP-4 inhibitors with metformin or other combination partners are described in PCT/EP2009053978, the disclosure of which is incorporated herein in its entirety. Typical dosage strengths of the dual combination of
BI 1356/metformin are 2.5/500 mg, 2.5/850 mg and 2.5/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily. - With respect to embodiment B, the methods of synthesis for the DPP-4 inhibitors of embodiment B are described in the scientific literature and/or in published patent documents, particularly in those cited herein.
- For pharmaceutical application in warm-blooded vertebrates, particularly humans, the compounds of this invention are usually used in dosages from 0.001 to 100 mg/kg body weight, preferably at 0.1-15 mg/kg, in each case 1 to 4 times a day. For this purpose, the compounds, optionally combined with other active substances, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
- The pharmaceutical compositions according to this invention comprising the DPP-4 inhibitors as defined herein are thus prepared by the skilled person using pharmaceutically acceptable formulation excipients as described in the art. Examples of such excipients include, without being restricted to diluents, binders, carriers, fillers, lubricants, flow promoters, crystallisation retardants, disintegrants, solubilizers, colorants, pH regulators, surfactants and emulsifiers.
- Examples of suitable diluents for compounds according to embodiment A include cellulose powder, calcium hydrogen phosphate, erythritol, low substituted hydroxypropyl cellulose, mannitol, pregelatinized starch or xylitol.
- Examples of suitable lubricants for compounds according to embodiment A include talc, polyethyleneglycol, calcium behenate, calcium stearate, hydrogenated castor oil or magnesium stearate.
- Examples of suitable binders for compounds according to embodiment A include copovidone (copolymerisates of vinylpyrrolidon with other vinylderivates), hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), polyvinylpyrrolidon (povidone), pregelatinized starch, or low-substituted hydroxypropylcellulose (L-HPC).
- Examples of suitable disintegrants for compounds according to embodiment A include corn starch or crospovidone.
- Suitable methods of preparing pharmaceutical formulations of the DPP-4 inhibitors according to embodiment A of the invention are
-
- direct tabletting of the active substance in powder mixtures with suitable tabletting excipients;
- granulation with suitable excipients and subsequent mixing with suitable excipients and subsequent tabletting as well as film coating; or
- packing of powder mixtures or granules into capsules.
- Suitable granulation methods are
-
- wet granulation in the intensive mixer followed by fluidised bed drying;
- one-pot granulation;
- fluidised bed granulation; or
- dry granulation (e.g. by roller compaction) with suitable excipients and subsequent tabletting or packing into capsules.
- For details on dosage forms, formulations and administration of DPP-4 inhibitors of this invention, reference is made to scientific literature and/or published patent documents, particularly to those cited herein.
- With respect to the first embodiment (embodiment A), the dosage typically required of the DPP-4 inhibitors mentioned herein in embodiment A when administered intravenously is 0.1 mg to 10 mg, preferably 0.25 mg to 5 mg, and when administered orally is 0.5 mg to 100 mg, preferably 2.5 mg to 50 mg or 0.5 mg to 10 mg, more preferably 2.5 mg to 10 mg or 1 mg to 5 mg, in each case 1 to 4 times a day. Thus, e.g. the dosage of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine when administered orally may be 5 mg to 50 mg, 20 mg to 50 mg, 0.5 mg to 10 mg, or 2.5 mg to 10 mg or 1 mg to 5 mg per patient per day.
- A dosage form prepared with a pharmaceutical composition comprising a DPP-4 inhibitor mentioned herein in embodiment A contain the active ingredient in a dosage range of 0.1-100 mg. Thus, e.g. particular dosage strengths of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine are 0.5 mg, 1 mg, 2.5 mg, 5 mg and 10 mg.
- It will be appreciated that the amount of a compound of this invention required for use in treatment and/or prevention may vary, e.g. with the nature and stage of the disease or condition being treated and/or prevented.
- With respect to the second embodiment (embodiment B), the doses of DPP-4 inhibitors mentioned herein in embodiment B to be administered to mammals, for example human beings, of, for example, approximately 70 kg body weight, may be generally from about 0.5 mg to about 350 mg, for example from about 10 mg to about 250 mg, preferably 20-200 mg, more preferably 20-100 mg, of the active moiety per person per day, or from about 0.5 mg to about 20 mg, preferably 2.5-10 mg, per person per day, divided preferably into 1 to 4 single doses which may, for example, be of the same size. Single dosage strengths comprise, for example, 10, 25, 40, 50, 75, 100, 150 and 200 mg of the DPP-4 inhibitor active moiety.
- A dosage strength of the DPP-4 inhibitor sitagliptin is usually between 25 and 200 mg of the active moiety. A recommended dose of sitagliptin is 100 mg calculated for the active moiety (free base anhydrate) once daily. Unit dosage strengths of sitagliptin free base anhydrate (active moiety) are 25, 50, 75, 100, 150 and 200 mg. Particular unit dosage strengths of sitagliptin (e.g. per tablet) are 25, 50 and 100 mg. An equivalent amount of sitagliptin phosphate monohydrate to the sitagliptin free base anhydrate is used in the pharmaceutical compositions, namely, 32.13, 64.25, 96.38, 128.5, 192.75, and 257 mg, respectively. Adjusted dosages of 25 and 50 mg sitagliptin are used for patients with renal failure. Typical dosage strengths of the dual combination of sitagliptin/metformin are 50/500 mg and 50/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- A dosage range of the DPP-4 inhibitor vildagliptin is usually between 10 and 150 mg daily, in particular between 25 and 150 mg, 25 and 100 mg or 25 and 50 mg or 50 and 100 mg daily. Particular examples of daily oral dosage are 25, 30, 35, 45, 50, 55, 60, 80, 100 or 150 mg. In a more particular aspect, the daily administration of vildagliptin may be between 25 and 150 mg or between 50 and 100 mg. In another more particular aspect, the daily administration of vildagliptin may be 50 or 100 mg. The application of the active ingredient may occur up to three times a day, preferably one or two times a day. Particular dosage strengths are 50 mg or 100 mg vildagliptin. Typical dosage strengths of the dual combination of vildagliptin/metformin are 50/850 mg and 50/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- Alogliptin may be administered to a patient at a daily dose of between 5 mg/day and 250 mg/day, optionally between 10 mg and 200 mg, optionally between 10 mg and 150 mg, and optionally between 10 mg and 100 mg of alogliptin (in each instance based on the molecular weight of the free base form of alogliptin). Thus, specific dosage amounts that may be used include, but are not limited to 10 mg, 12.5 mg, 20 mg, 25 mg, 50 mg, 75 mg and 100 mg of alogliptin per day. Alogliptin may be administered in its free base form or as a pharmaceutically acceptable salt.
- Saxagliptin may be administered to a patient at a daily dose of between 2.5 mg/day and 100 mg/day, optionally between 2.5 mg and 50 mg. Specific dosage amounts that may be used include, but are not limited to 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg and 100 mg of saxagliptin per day. Typical dosage strengths of the dual combination of saxagliptin/metformin are 2.5/500 mg and 2.5/1000 mg, each of which may be administered orally once or twice daily, in particular twice daily.
- A special embodiment of the DPP-4 inhibitors of this invention refers to those orally administered DPP-4 inhibitors which are therapeutically efficacious at low dose levels, e.g. at oral dose levels <100 mg or <70 mg per patient per day, preferably <50 mg, more preferably <30 mg or <20 mg, even more preferably from 1 mg to 10 mg, particularly from 1 mg to 5 mg (more particularly 5 mg), per patient per day (if required, divided into 1 to 4 single doses, particularly 1 or 2 single doses, which may be of the same size, preferentially, administered orally once- or twice daily (more preferentially once-daily), advantageously, administered at any time of day, with or without food. Thus, for example, the daily oral amount 5
mg BI 1356 can be given in a once daily dosing regimen (i.e. 5mg BI 1356 once daily) or in a twice daily dosing regimen (i.e. 2.5mg BI 1356 twice daily), at any time of day, with or without food. - A particularly preferred DPP-4 inhibitor to be emphasized within the meaning of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine (also known as BI 1356).
BI 1356 exhibits high potency, 24 h duration of action, and a wide therapeutic window. In people withtype 2diabetes BI 1356 shows a placebo-like safety and tolerability. With low doses of about ≧5 mg,BI 1356 acts as a true once-daily oral drug with a full 24 h duration of DPP-4 inhibition. At therapeutic oral dose levels,BI 1356 is mainly excreted via the liver and only to a minor extent (about <7% of the administered oral dose) via the kidney.BI 1356 is primarily excreted unchanged via the bile. The fraction ofBI 1356 eliminated via the kidneys increases only very slightly over time and with increasing dose, so that there will likely be no need to modify the dose ofBI 1356 based on the patients' renal function. The non-renal elimination ofBI 1356 in combination with its low accumulation potential and broad safety margin may be of significant benefit in a diabetes patient population that has a high prevalence of renal insufficiency and diabetic nephropathy. - As different metabolic functional disorders often occur simultaneously, it is quite often indicated to combine a number of different active principles with one another. Thus, depending on the functional disorders diagnosed, improved treatment outcomes may be obtained if a DPP-4 inhibitor is combined with active substances customary for the respective disorders, such as e.g. one or more active substances selected from among the other antidiabetic substances, especially active substances that lower the blood sugar level or the lipid level in the blood, raise the HDL level in the blood, lower blood pressure or are indicated in the treatment of atherosclerosis or obesity. Further, within the meaning of this invention, optionally in addition, a DPP-4 inhibitor may be combined with one or more antioxidants and/or anti-inflammatory agents. Yet further, within the meaning of this invention, optionally in addition, a DPP-4 inhibitor may be combined with one or more vascular endothelial protective agents.
- The DPP-4 inhibitors mentioned above—besides their use in mono-therapy—may also be used in conjunction with other active substances, by means of which improved treatment results can be obtained. Such a combined treatment may be given as a free combination of the substances or in the form of a fixed combination, for example in a tablet or capsule. Pharmaceutical formulations of the combination partner(s) needed for this may either be obtained commercially as pharmaceutical compositions or may be formulated by the skilled man using conventional methods. The active substances which may be obtained commercially as pharmaceutical compositions are described in numerous places in the prior art, for example in the list of drugs that appears annually, the “Rote Liste®” of the federal association of the pharmaceutical industry, or in the annually updated compilation of manufacturers' information on prescription drugs known as the “Physicians' Desk Reference”.
- Examples of antidiabetic combination partners are metformin; sulphonylureas such as glibenclamide, tolbutamide, glimepiride, glipizide, gliquidon, glibornuride and gliclazide; nateglinide; repaglinide; thiazolidinediones such as rosiglitazone and pioglitazone; PPAR gamma modulators such as metaglidases; PPAR-gamma agonists such as GI 262570; PPAR-gamma antagonists; PPAR-gamma/alpha modulators such as tesaglitazar, muraglitazar and KRP297; PPAR-gamma/alpha/delta modulators; AMPK-activators such as AICAR; acetyl-CoA carboxylase (ACC1 and ACC2) inhibitors; diacylglycerol-acetyltransferase (DGAT) inhibitors; pancreatic beta cell GCRP agonists such as SMT3-receptor-agonists and GPR119; 11β-HSD-inhibitors; FGF19 agonists or analogues; alpha-glucosidase blockers such as acarbose, voglibose and miglitol; alpha2-antagonists; insulin and insulin analogues such as human insulin, insulin lispro, insulin glusilin, r-DNA-insulinaspart, NPH insulin, insulin detemir, insulin zinc suspension and insulin glargin; Gastric inhibitory Peptide (GIP); pramlintide; amylin or GLP-1 and GLP-1 analogues such as Exendin-4, e.g. exenatide, exenatide LAR, liraglutide, taspoglutide or albiglutide; SGLT2-inhibitors such as KGT-1251; inhibitors of protein tyrosine-phosphatase; inhibitors of glucose-6-phosphatase; fructose-1,6-bisphosphatase modulators; glycogen phosphorylase modulators; glucagon receptor antagonists; phosphoenolpyruvatecarboxykinase (PEPCK) inhibitors; pyruvate dehydrogenasekinase (PDK) inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); glucokinase/regulatory protein modulators incl. glucokinase activators; glycogen synthase kinase inhibitors; inhibitors of the SH2-domain-containing inositol 5-phosphatase type 2 (SHIP2); IKK inhibitors such as high-dose salicylate; JNK1 inhibitors; protein kinase C-theta inhibitors;
beta 3 agonists such as ritobegron, YM 178, solabegron, talibegron, N-5984, GRC-1087, rafabegron, FMP825; aldosereductase inhibitors such as AS 3201, zenarestat, fidarestat, epalrestat, ranirestat, NZ-314, CP-744809, and CT-112; SGLT-1 or SGLT-2 inhibitors; KV 1.3 channel inhibitors; GPR40 modulators; SCD-1 inhibitors; CCR-2 antagonists; dopamine receptor agonists (bromocriptine mesylate/Cycloset); and other DPP IV inhibitors. - A preferred example of an antidiabetic combination partner is metformin, which is usually given in doses varying from about 250 mg to 3000 mg, particularly from 500 mg to 2000 mg up to 2500 mg per day using various dosing regimens, such as e.g. usually in doses of about 100 mg to 500 mg or 200 mg to 850 mg (1-3 times a day), or about 300 mg to 1000 mg once or twice a day, or delayed-release metformin in doses of about 100 mg to 1000 mg or preferably 500 mg to 1000 mg once or twice a day or about 500 mg to 2000 mg once a day. Particular dosage strengths may be 250, 500, 625, 750, 850 and 1000 mg of metformin hydrochloride.
- Another preferred example is pioglitazone, usually in a dosage of about 1-10 mg, 15 mg, 30 mg, or 45 mg once a day.
- Rosiglitazone is usually given in doses from 4 to 8 mg once (or divided twice) a day (typical dosage strengths are 2, 4 and 8 mg).
- Glibenclamide (glyburide) is usually given in doses from 2.5-5 to 20 mg once (or divided twice) a day (typical dosage strengths are 1.25, 2.5 and 5 mg), or micronized glibenclamide in doses from 0.75-3 to 12 mg once (or divided twice) a day (typical dosage strengths are 1.5, 3, 4.5 and 6 mg).
- Glipizide is usually given in doses from 2.5 to 10-20 mg once (up to 40 mg divided twice) a day (typical dosage strengths are 5 and 10 mg), or extended-release glipizide in doses from 5 to 10 mg (up to 20 mg) once a day (typical dosage strengths are 2.5, 5 and 10 mg).
- Glimepiride is usually given in doses from 1-2 to 4 mg (up to 8 mg) once a day (typical dosage strengths are 1, 2 and 4 mg).
- A dual combination of glibenclamide/metformin is usually given in doses from 1.25/250 once daily to 10/1000 mg twice daily (typical dosage strengths are 1.25/250, 2.5/500 and 5/500 mg).
- A dual combination of glipizide/metformin is usually given in doses from 2.5/250 to 10/1000 mg twice daily (typical dosage strengths are 2.5/250, 2.5/500 and 5/500 mg).
A dual combination of glimepiride/metformin is usually given in doses from 1/250 to 4/1000 mg twice daily. - A dual combination of rosiglitazone/glimepiride is usually given in doses from 4/1 once or twice daily to 4/2 mg twice daily (typical dosage strengths are 4/1, 4/2, 4/4, 8/2 and 8/4 mg). A dual combination of pioglitazone/glimepiride is usually given in doses from 30/2 to 30/4 mg once daily (typical dosage strengths are 30/4 and 45/4 mg).
- A dual combination of rosiglitazone/metformin is usually given in doses from 1/500 to 4/1000 mg twice daily (typical dosage strengths are 1/500, 2/500, 4/500, 2/1000 and 4/1000 mg). A dual combination of pioglitazone/metformin is usually given in doses from 15/500 once or twice daily to 15/850 mg thrice daily (typical dosage strengths are 15/500 and 15/850 mg).
- The non-sulphonylurea insulin secretagogue nateglinide is usually given in doses from 60 to 120 mg with meals (up to 360 mg/day, typical dosage strengths are 60 and 120 mg); repaglinide is usually given in doses from 0.5 to 4 mg with meals (up to 16 mg/day, typical dosage strengths are 0.5, 1 and 2 mg). A dual combination of repaglinide/metformin is available in dosage strengths of 1/500 and 2/850 mg.
- Acarbose is usually given in doses from 25 to 100 mg with meals (up to 300 mg/day, typical dosage strengths are 25, 50 and 100 mg). Miglitol is usually given in doses from 25 to 100 mg with meals (up to 300 mg/day, typical dosage strengths are 25, 50 and 100 mg).
- Examples of combination partners that lower the lipid level in the blood are HMG-CoA-reductase inhibitors such as simvastatin, atorvastatin, lovastatin, fluvastatin, pravastatin and rosuvastatin; fibrates such as bezafibrate, fenofibrate, clofibrate, gemfibrozil, etofibrate and etofyllinclofibrate; nicotinic acid and the derivatives thereof such as acipimox; PPAR-alpha agonists; PPAR-delta agonists; inhibitors of acyl-coenzyme A:cholesterolacyltransferase (ACAT; EC 2.3.1.26) such as avasimibe; cholesterol resorption inhibitors such as ezetimib; substances that bind to bile acid, such as cholestyramine, colestipol and colesevelam; inhibitors of bile acid transport; HDL modulating active substances such as D4F, reverse D4F, LXR modulating active substances and FXR modulating active substances; CETP inhibitors such as torcetrapib, JTT-705/dalcetrapib, anacetrapib or compound 12 from WO 2007/005572; LDL receptor modulators; and ApoB100 antisense RNA.
- A dosage of the partner drug atorvastatin is usually from 1 mg to 40 mg or 10 mg to 80 mg once a day
- Examples of combination partners that lower blood pressure are beta-blockers such as atenolol, bisoprolol, celiprolol, metoprolol and carvedilol; diuretics such as hydrochlorothiazide, chlortalidon, xipamide, furosemide, piretanide, torasemide, spironolactone, eplerenone, amiloride and triamterene; calcium channel blockers such as amlodipine, nifedipine, nitrendipine, nisoldipine, nicardipine, felodipine, lacidipine, lercanipidine, manidipine, isradipine, nilvadipine, verapamil, gallopamil and diltiazem; ACE inhibitors such as ramipril, lisinopril, cilazapril, quinapril, captopril, enalapril, benazepril, perindopril, fosinopril and trandolapril; as well as angiotensin II receptor blockers (ARBs) such as telmisartan, candesartan, valsartan, losartan, irbesartan, olmesartan and eprosartan.
- A dosage of the partner drug telmisartan is usually from 20 mg to 320 mg or 40 mg to 160 mg per day.
- Examples of combination partners which increase the HDL level in the blood are Cholesteryl Ester Transfer Protein (CETP) inhibitors; inhibitors of endothelial lipase; regulators of ABC1; LXRalpha antagonists; LXRbeta agonists; PPAR-delta agonists; LXRalpha/beta regulators, and substances that increase the expression and/or plasma concentration of apolipoprotein A-I.
- Examples of combination partners for the treatment of obesity are sibutramine; tetrahydrolipstatin (orlistat); alizyme; dexfenfluramine; axokine; cannabinoid receptor 1 antagonists such as the CB1 antagonist rimonobant; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 as well as NPY2 antagonists; beta3-AR agonists such as SB-418790 and AD-9677; 5HT2c receptor agonists such as APD 356; myostatin inhibitors; Acrp30 and adiponectin; steroyl CoA desaturase (SCD1) inhibitors; fatty acid synthase (FAS) inhibitors; CCK receptor agonists; Ghrelin receptor modulators; Pyy 3-36; orexin receptor antagonists; and tesofensine.
- Examples of combination partners for the treatment of atherosclerosis are phospholipase A2 inhibitors; inhibitors of tyrosine-kinases (50 mg to 600 mg) such as PDGF-receptor-kinase (cf. EP-A-564409, WO 98/35958, U.S. Pat. No. 5,093,330, WO 2004/005281, and WO 2006/041976); oxLDL antibodies and oxLDL vaccines; apoA-1 Milano; ASA; and VCAM-1 inhibitors.
- Examples of antioxidant combination partners are selenium, betaine, vitamin C, vitamin E and beta carotene.
- An example of an anti-inflammatory combination partner is pentoxifylline; another example of an anti-inflammatory combination partner is a PDE-4 inhibitor, such as e.g. tetomilast, roflumilast, or 3-[7-ethyl-2-(methoxymethyl)-4-(5-methyl-3-pyridinyl)pyrrolo[1,2-b]pyridazin-3-yl]propanoic acid (or other species disclosed in U.S. Pat. No. 7,153,854, WO 2004/063197, U.S. Pat. No. 7,459,451 and/or WO 2006/004188).
- A further example of an anti-inflammatory partner drug is a caspase inhibitor, such as e.g. (3S)-5-fluoro-3-({[(5R)-5-isopropyl-3-(1-isoquinolinyl)-4,5-dihydro-5-isoxazolyl]carbonyl}amino-4-oxopentanoic acid (or other species disclosed in WO 2005/021516 and/or WO 2006/090997).
- An example of a vascular endothelial protective agent is a PDE-5 inhibitor, such as e.g. sildenafil, vardenafil or tadalafil; another example of a vascular endothelial protective agent is a nitric oxide donor.
- Further, within the meaning of this invention, optionally in addition, a DPP-4 inhibitor may be combined with one or more CCK-2 or gastrin agonists, such as e.g. proton pump inhibitors (including reversible as well as irreversible inhibitors of the gastric H+/K+-ATPase), for example omeprazole, esomeprazole, pantoprazole, rabeprazole or lansoprazole.
- A particularly preferred DPP-4 inhibitor to be emphasized within the meaning of this invention is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine free base (also known as BI 1356).
- The present invention is not to be limited in scope by the specific embodiments described herein. Various modifications of the invention in addition to those described herein may become apparent to those skilled in the art from the present disclosure. Such modifications are intended to fall within the scope of the appended claims.
- All patent applications cited herein are hereby incorporated by reference in their entireties.
- Further embodiments, features and advantages of the present invention may become apparent from the following examples. The following examples serve to further illustrate, by way of example, the principles of the invention without restricting it, and/or to aid in the understanding of the invention but are not construed as a limitation.
- Animals and Special Diets
- a) Female db/db mice [C57BLKS/Bom-db/db; Charles-River, Germany], aged 6-7 weeks at start are treated 8 weeks with the DPP-4 inhibitor. Animals are kept in groups of 5-6 mice in Makrolon® cages with free access to food and tap water. The room is maintained as follows: dark light rhythm [6 a.m. to 6 p.m. light], room temperature 22±2° C., relative humidity 50±10%.
- The DPP-4 inhibitor is suspended in 0.5% [w/v] natrosol. Single daily oral administrations of 3 mg/kg/d of the DPP-4 inhibitor in a volume of 5 ml/kg by gavage are performed. Control animals receive 0.5% [w/v] natrosol, also in a volume of 5 ml/kg. At the end of the treatment period [8 weeks after treatment start] animals are dissected and liver biopsies taken.
- b) Male ZDF rats (ZDF/Crl-leprfa), age 8-10 weeks at start are treated daily with the DPP-4 inhibitor for 35 days in a dose of 3 mg/kg/d. The application volume is 3 ml/kg natrosol. Animal (n=8-10) are houses in single cages. The room is maintained as follows: dark light rhythm [6 a.m. to 6 p.m. light], room temperature 22±2° C., relative humidity 50±10%.
- c) Diet induced steatosis: Male C57BL/6 mice [C57BL/6NC] supplied by Charles River, Germany] are fed with a high fat diet [D12492, 60% kcal of fat, 5.24 kcal/g, Research diets, New Brunswick, USA] starting in the age of 9 weeks. Animals receive chow and water ad libitum. They are kept under controlled conditions and dark light rhythm [6 a.m. to 6 p.m. light]. Animals receive the high fat diet for 7 weeks before treatment start. Thereafter, animals are treated with the DPP-4 inhibitor (0.1-10 mg/kg/d orally, suspended in 0.5% natrosol or vehicle for 6 weeks once daily). Animals are sacrificed following an overnight fast and livers are removed for further analysis.
- d) MCD induced steatosis: Male C57BL/6 mice [C57BL/6NC] supplied by Charles River, Germany] are allowed to normal diet or a MCD (methionine and cholin deficient diet) (Research Diets, New Brunswick, USA) and tap water ad libitum throughout the experimental period. At first, all mice are fed the normal diet during a 1-week quarantine and acclimation period. Then, at 9 weeks of age, mice displaying no abnormal findings at the end of the quarantine and acclimation period are randomly divided into groups (8-10 mice/group) and are treated for 5 weeks as follows: group 1 (normal), fed normal diet plus vehicle (0.5% [w/v] natrosol); group 2 (MCD control), fed MCD diet plus vehicle;
group 3, fed MCD diet plus the DPP-4 inhibitor (3 mg/kg/day). At the end of the experimental period, blood samples are collected from the tail vein of the mice and the livers are collected. Histological analysis of inflammation and fibrosis are performed like under necropsy and histology. - Detection of Liver Triglyceride Content
- Samples for hepatic triglycerides measurement are generated by homogenizing a liver lobe in lysis buffer (0.5
% polyoxyethylen 10 tridecylether (Sigma, P 2393), 0.01 M NaPi, 1 mM EDTA, pH 7.4). The liver tissue is previously heated in thesame buffer 10 min to 95° C. Following the initial homogenization, samples are further processed using the MP Biotech (FastPrep-24) equipment and orange caps (2×45 s). Samples are then centrifuged 2 min at 3000 rpm. The supernatant is collected for further analysis. Triglyceride content is measured using the Sigma serum triglyceride kit (Sigma, TR 0100). - Necropsy and Histology
- Necropsy is performed in ad libitum fed animals. Animals are anesthetized with 3% isoflurane/oxygen [Isoba®, batch J10417, Essex Pharma GmbH, 81737, Germany]. The liver is removed and fixed in 4% paraformaldhyd solution for later microscopic. Liver lipidosis is evaluated blinded and semi-quantitatively by light microscopy. The slides are blindly examinated on coded slides and all parameters (e.g. steatosis, inflammation) are semi-quantitatively scored (severity index) by the following scheme:
- Score 1=no changes
Score 2=minimal changes (<5% of liver tissues affected)
Score 3=mild changes (5-15% of liver tissue affected)
Score 4=moderate changes (15-25% of liver tissue affected)
Score 5=severe changes (>25% of liver tissue affected) - Determination of Liver Steatosis by Means of NMR Spectroscopy
- For the in vivo measurement of liver lipid content by NMR spectroscopy, C57BL/6 mice with diet-induced steatosis are anesthetised by continuous inhalation of 2% isoflurane in a N2O:O2, (70:30, v:v) gas mixture. NMR measurements are performed on a Bruker BioSpec 47/40 scanner (Bruker BioSpin, Ettlingen, Germany) equipped with a BGA12 gradient coil system. A volume coil is used for excitation, a surface coil for signal reception. For anatomical orientation a pilot scan comprising horizontal and axial MR images is acquired using a gradient-echo pulse sequence with the following parameters: TR 135 ms, TE 3.5 ms, field-of view 45×45 mm2, matrix 1282, slice thickness 1.75 mm. According to the pilot scan, a voxel-of-interest (VOI, 3×3×3 mm3) is placed in the left ventral part of the liver. Liver lipids in the VOI are measured by NMR spectroscopy using a PRESS sequence (point-resolved spectroscopy) with the following parameters: TR 1050 ms,
TE 20 ms, number of averages 32, digital resolution 1024 data points. Data are analyzed using the commercially available software package LCModel by S. W. Provencher. - In animal model c) described above (diet induced obesity mice) the following results are obtained for BI 1356:
-
DIO mice 2 months on high fat diet (liverfat day 29 following treatment/control):FIG. 1 -
DIO mice 4 months on high fat diet (liverfat day 21 following treatment/control):FIG. 2 - The effect on fatty liver diseases of the DPP-4 inhibitors of this invention can be tested in the models given herein and/or studied and detected by the methods described hereinabove and hereinbelow. The effect on various forms of fibrosis can be studied via the following detection methods:
- Quantitative Measurements of Specific mRNAs by RT-PCR
- After disruption and homogenization in lysis buffer approximatively 50 mg snap frozen tissue, total RNA is isolated using a RNeasy Mini-kit (Qiagen, Germany). Transcripts for collagen type I, TGF-β1, procollagen α1(I), TIMP-1 (tissue inhibitor of matrix metalloproteinases-1),
metalloproteases - Sirius Red Staining of Collagen
- Sections 5 μm thick from formalin fixed, paraffin embedded tissue are prepared and are stained with Sirius red (saturated picric acid in distillated water containing 0.1% (w/v) Sirius red F3B (BDH Chemicals, UK) to allow visualisation of liver fibrosis. All samples from a series of experiments are stained simultaneously and evaluated in a blinded fashion.
- Necropsy and Histology
- Necropsy is performed in ad libitum fed animals. Animals are anesthetized with 3% isoflurane/oxygen [Isoba®, batch J10417, Essex Pharma GmbH, 81737, Germany]. The organs (liver, kidney, lung, etc.) are removed and fixed in 4% paraformaldhyd solution for later microscopic. Fibrosis is evaluated blinded and semi-quantitatively by light microscopy. The slides are blindly examinated on coded slides and all parameters are semi-quantitatively scored (severity index) by the following scheme1: 1) Ishak etal. J Hepatol 22: 696, 1995
- Score 0=no fibrosis
Score 1=some portal tracts expanded
Score 2=most portal tracts expanded
Score 3=most portal tracts expended, +/−links
Score 4=marked bridging (P-P and P-C links)
Score 5=marked bridging, occasional nodules (incomplete cirrhosis)
Score 6=cirrhosis, probably or definite - Determination of Fibrosis by Means of Magnetic Resonance Elastography
- Fibrosis is associated with increased stiffness and viscosity of the tissue. The viscoelastic properties of living tissue can be assessed with Magnetic Resonance Elastography (MRE) by measuring the propagation of low-frequency mechanical shear waves through the tissue. The propagation of the shear waves is visualized by non-invasive Magnetic Resonance Imaging (MRI), from which parameters for the mechanical properties of the tissue can be derived. Preclinical studies have shown that MRE can differentiate between the known stages of fibrosis and that the methods' results correspond with those of the gold-standard of biopsy2. 2) Salameh et al. J. Magn. Reson. Imaging 26:956, 2007
- Effect on Body Weight:
FIG. 3
Claims (21)
1. A method of treating and/or preventing a non alcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof an effective amount of a DPP-4 inhibitor of formula (I)
or of formula (II)
or of formula (III)
or of formula (IV)
wherein R1 denotes ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl and R2 denotes 3-(R)-amino-piperidin-1-yl, (2-amino-2-methyl-propyl)-methylamino or (2-(S)-amino-propyl)-methylamino,
or its pharmaceutically acceptable salt.
2. A method of treating and/or preventing a non alcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof an effective amount of a DPP-4 inhibitor selected from the group consisting of
sitagliptin, vildagliptin, saxagliptin, alogliptin,
(2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,
(3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,
(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,
(2S,4S)-1-{2-[(3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile,
(R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile, and
5-{(S)-2-[2-((S)-2-Cyano-pyrrolidin-1-yl)-2-oxo-ethylamino]-propyl}-5-(1H-tetrazol-5-yl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-2,8-dicarboxylic acid bis-dimethylamide,
1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,
1-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine,
1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine,
2-((R)-3-amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(4-methyl-quinazolin-2-ylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one,
1-[4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[2-amino-2-methyl-propyl)-methylamino]-xanthine,
1-[3-cyano-quinolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine,
1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,
1-[4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl)-methylamino]-xanthine,
1-[3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine,
1-[4-methyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine,
1-[4,6-dimethyl-pyrimidin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine and
1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(R)-3-amino-piperidin-1-yl)-xanthine,
or a pharmaceutically acceptable salt thereof.
3. The method according to claim 2 , wherein said DPP-4 inhibitor is selected from the group consisting of
sitagliptin, vildagliptin, saxagliptin, alogliptin,
(2S)-1-{[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(2S)-1-{[1,1,-Dimethyl-3-(4-pyridin-3-yl-imidazol-1-yl)-propylamino]-acetyl}-pyrrolidine-2-carbonitrile,
(S)-1-((2S,3S,11bS)-2-Amino-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-3-yl)-4-fluoromethyl-pyrrolidin-2-one,
(3,3-Difluoropyrrolidin-1-yl)-((2S,4S)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone,
(1((3S,4S)-4-amino-1-(4-(3,3-difluoropyrrolidin-1-yl)-1,3,5-triazin-2-yl)pyrrolidin-3-yl)-5,5-difluoropiperidin-2-one,
(2S,4S)-1-{2-[3S,1R)-3-(1H-1,2,4-Triazol-1-ylmethyl)cyclopentylamino]-acetyl}-4-fluoropyrrolidine-2-carbonitrile, and
(R)-2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile,
or a pharmaceutically acceptable salt thereof.
4. The method according to claim 2 , wherein said DPP-4 inhibitor is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.
5. The method according to claim 1 , wherein said NALFD is selected from the group consisting of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and liver fibrosis.
6. The method according to claim 5 wherein said NAFLD is hepatic steatosis.
7. The method according to claim 5 wherein said NAFLD is non-alcoholic steatohepatitis (NASH).
8. The method according to claim 5 wherein said NAFLD is liver fibrosis.
9. A method of using a pharmaceutical composition comprising a DPP-4 inhibitor according to claim 1 for treating and/or preventing a non alcoholic fatty liver disease (NAFLD) selected from the group consisting of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis.
10. The method according to claim 9 wherein said pharmaceutical composition further comprises metformin.
11. The method according to claim 9 wherein said pharmaceutical composition further comprises pioglitazone.
12-13. (canceled)
14. The method according to claim 9 , wherein the pharmaceutical composition further comprises one or more other active substances selected from the group consisting of antidiabetic substances, active substances used to lower the lipid level in the blood, active substances used to raise the HDL level in the blood, active substances used to lower blood pressure, active substances used for treating atherosclerosis, active substances used for treating obesity, antioxidants, and anti-inflammatory agents, wherein said other active substances are administered in a manner that is separate, sequential, simultaneous, concurrent or chronologically staggered from the DPP-IV inhibitor.
15. The method according to claim 5 further comprising one or more other active substances selected from the group consisting of antidiabetic substances, active substances used to lower the lipid level in the blood, active substances used to raise the HDL level in the blood, active substances used to lower blood pressure, active substances used for treating atherosclerosis, active substances used for treating obesity, antioxidants, and anti-inflammatory agents.
16. The method according to claim 15 , wherein said other active substances is selected from the group consisting of biguanides, thiazolidinones, statines, and angiotensin II receptor blockers.
17. (canceled)
18. A method of treating and/or preventing a non alcoholic fatty liver disease (NAFLD) comprising administering to a patient in need thereof an effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine.
19. The method according to claim 18 , wherein said NALFD is selected from the group consisting of hepatic steatosis, non-alcoholic steatohepatitis (NASH) and/or liver fibrosis.
20. The method according to claim 18 further comprising one or more other active substances selected from the group consisting of antidiabetic substances, including active substances used to lower the blood sugar level, active substances used to lower the lipid level in the blood, active substances used to raise the HDL level in the blood, active substances used to lower blood pressure, active substances used for treating atherosclerosis, active substances used for treating obesity, antioxidants, and anti-inflammatory agents.
21. The method according to claim 20 wherein said other active substance is metformin.
22. The method according to claim 20 wherein said other active substance is pioglitazone.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/995,474 US20110092510A1 (en) | 2008-06-03 | 2009-06-02 | Dpp-iv inhibitors for use in the treatment of nafld |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08157512 | 2008-06-03 | ||
EP08157512.8 | 2008-06-03 | ||
US8734908P | 2008-08-08 | 2008-08-08 | |
EP09152297 | 2009-02-06 | ||
EP09152297.9 | 2009-02-06 | ||
US15307409P | 2009-02-17 | 2009-02-17 | |
US12/995,474 US20110092510A1 (en) | 2008-06-03 | 2009-06-02 | Dpp-iv inhibitors for use in the treatment of nafld |
PCT/EP2009/056722 WO2009147125A1 (en) | 2008-06-03 | 2009-06-02 | Dpp-iv inhibitors for use in the treatment of nafld |
Publications (1)
Publication Number | Publication Date |
---|---|
US20110092510A1 true US20110092510A1 (en) | 2011-04-21 |
Family
ID=40910764
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/995,474 Abandoned US20110092510A1 (en) | 2008-06-03 | 2009-06-02 | Dpp-iv inhibitors for use in the treatment of nafld |
Country Status (22)
Country | Link |
---|---|
US (1) | US20110092510A1 (en) |
EP (2) | EP3348263A1 (en) |
JP (2) | JP2011521003A (en) |
KR (2) | KR101750693B1 (en) |
CN (2) | CN102056606B (en) |
AR (1) | AR071992A1 (en) |
AU (1) | AU2009253937B2 (en) |
CA (1) | CA2726244C (en) |
CO (1) | CO6280472A2 (en) |
EA (1) | EA023207B1 (en) |
EC (1) | ECSP10010697A (en) |
ES (1) | ES2660417T3 (en) |
HK (1) | HK1201195A1 (en) |
IL (2) | IL208811A0 (en) |
MA (1) | MA32372B1 (en) |
MX (2) | MX350455B (en) |
NZ (1) | NZ588843A (en) |
PE (1) | PE20100156A1 (en) |
SG (1) | SG192400A1 (en) |
TW (1) | TW201002718A (en) |
UY (1) | UY31858A (en) |
WO (1) | WO2009147125A1 (en) |
Cited By (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8106060B2 (en) | 2005-07-30 | 2012-01-31 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US8119648B2 (en) | 2002-08-21 | 2012-02-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8232281B2 (en) | 2006-05-04 | 2012-07-31 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US8513264B2 (en) | 2008-09-10 | 2013-08-20 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
US20130244932A1 (en) * | 2012-02-24 | 2013-09-19 | Wisconsin Alumni Research Foundation | E-prostanoid receptor, ptger3, as a novel anti-diabetic therapeutic target |
US8541450B2 (en) | 2004-11-05 | 2013-09-24 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines |
US8551957B2 (en) | 2007-08-16 | 2013-10-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate |
US8697868B2 (en) | 2004-02-18 | 2014-04-15 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
US8846695B2 (en) | 2009-01-07 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor |
US8853156B2 (en) | 2008-08-06 | 2014-10-07 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8865729B2 (en) | 2008-12-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Salt forms of a xanthine compound |
US8883800B2 (en) | 2011-07-15 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US9149478B2 (en) | 2010-06-24 | 2015-10-06 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
US9155705B2 (en) | 2008-04-03 | 2015-10-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9186392B2 (en) | 2010-05-05 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
US20150335715A1 (en) * | 2013-01-03 | 2015-11-26 | Oramed Ltd. | Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof |
US9266888B2 (en) | 2006-05-04 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Polymorphs |
WO2016085994A1 (en) * | 2014-11-26 | 2016-06-02 | Medicinova, Inc. | Ibudilast and telmisartan for treating non-alcoholic fatty liver disease, non alcoholic steatohepatitis, and advanced non alcoholic steatohepatitis |
EA023747B1 (en) * | 2014-11-13 | 2016-07-29 | Промомед Холдингс Лимитед | Pharmaceutical composition for preventing and treating overweight or obesity related disorders (variants), kits (variants), use thereof and method of preventing and treating overweight or obesity related disorders |
US9457029B2 (en) | 2009-11-27 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9486526B2 (en) | 2008-08-06 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
US9526730B2 (en) | 2012-05-14 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
WO2017083433A1 (en) * | 2015-11-09 | 2017-05-18 | Cortexyme, Inc. | Inhibitors of arginine gingipain |
US9713618B2 (en) | 2012-05-24 | 2017-07-25 | Boehringer Ingelheim International Gmbh | Method for modifying food intake and regulating food preference with a DPP-4 inhibitor |
US20180185291A1 (en) | 2011-03-07 | 2018-07-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
US10058593B2 (en) | 2008-03-26 | 2018-08-28 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
US10406172B2 (en) | 2009-02-13 | 2019-09-10 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
WO2020236890A1 (en) * | 2019-05-20 | 2020-11-26 | Mayo Foundation For Medical Education And Research | Treating chronic liver disease |
US10857136B2 (en) | 2017-03-14 | 2020-12-08 | Sjt Molecular Research, Sl | Compounds for use in the prevention and/or treatment of non-alcoholic fat liver disease and non-alcoholic steatohepatitis |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SG183817A1 (en) * | 2010-03-24 | 2012-10-30 | Dong A Pharm Co Ltd | Pharmaceutical composition for the prevention or the treatment of non-alcoholic fatty liver disease and the method for prevention or treatment of non-alcoholic fatty liver disease using the same |
US8691832B2 (en) * | 2010-12-06 | 2014-04-08 | Merck Sharp & Dohme Corp. | Tricyclic heterocycles useful as dipeptidyl peptidase-IV inhibitors |
EP2498195A1 (en) * | 2011-03-11 | 2012-09-12 | Centre Hospitalier Universitaire d'Angers | Non-invasive method for assessing the presence or severity of liver fibrosis based on a new detailed classification |
US9233102B2 (en) | 2012-03-07 | 2016-01-12 | Mayo Foundation For Medical Education And Research | Methods and materials for treating cancer |
ES2929025T3 (en) * | 2012-05-14 | 2022-11-24 | Boehringer Ingelheim Int | Linagliptin, a xanthine derivative as a dpp-4 inhibitor, for use in the treatment of SIRS and/or sepsis |
WO2013174768A1 (en) * | 2012-05-24 | 2013-11-28 | Boehringer Ingelheim International Gmbh | A xanthine derivative as dpp -4 inhibitor for use in the treatment of autoimmune diabetes, particularly lada |
CN104721188A (en) * | 2013-12-20 | 2015-06-24 | 中美华世通生物医药科技(武汉)有限公司 | Stable composition containing Alogliptin benzoate |
CN105384724A (en) * | 2014-09-01 | 2016-03-09 | 广东东阳光药业有限公司 | Fluoro-compound crystalline form and preparation method therefor |
TW201613600A (en) * | 2014-09-02 | 2016-04-16 | Jansfat Biotechnology Co Ltd | Piperazinyl derivative reduces HFD-induced accumulation of fat in the liver, therapeutically |
TWI772252B (en) * | 2014-09-16 | 2022-08-01 | 南韓商韓美藥品股份有限公司 | Use of a long acting glp-1/glucagon receptor dual agonist for the treatment of non-alcoholic fatty liver disease |
MA41120A (en) * | 2014-12-02 | 2017-10-10 | Afimmune Ltd | COMPOSITIONS INCLUDING 15-HEPE AND METHODS OF TREATING OR PREVENTING FIBROSIS USING THEM |
WO2016173923A1 (en) | 2015-04-28 | 2016-11-03 | Pronova Biopharma Norge As | Use of structurally enhanced fatty acids containing sulphur for preventing and/or treating non-alcoholic steatohepatitis |
TWI682931B (en) * | 2015-05-29 | 2020-01-21 | 大陸商江蘇天士力帝益藥業有限公司 | Xanthine derivatives, their pharmaceutical compositions, their preparations and their uses |
US11605460B2 (en) | 2016-01-08 | 2023-03-14 | Centre Hospitalier Universitaire D'angers | Multi-targeted fibrosis tests |
JP2019077615A (en) * | 2016-03-09 | 2019-05-23 | 公立大学法人和歌山県立医科大学 | Therapeutic agents for non-alcoholic fatty liver diseases/non-alcoholic steatohepatitis |
BR112018069789A2 (en) * | 2016-03-28 | 2019-01-29 | Intercept Pharmaceuticals Inc | medicine obtained by combining fxr and arb agonist |
JP2019517523A (en) * | 2016-06-03 | 2019-06-24 | ケモセントリックス, インコーポレイテッド | How to treat liver fibrosis |
MX2020005621A (en) | 2017-12-06 | 2020-08-20 | Basf As | Fatty acid derivatives for treating non-alcoholic steatohepatitis. |
JP2021513552A (en) * | 2018-02-14 | 2021-05-27 | ルーモス ファーマ,インコーポレイティド | Compositions for the treatment of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis |
KR102510783B1 (en) | 2018-03-09 | 2023-03-15 | 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 | Novel drug use of thieno[3,2-d]pyrimidin-4-one compounds |
CN110934866B (en) * | 2018-09-25 | 2023-12-01 | 深圳微芯生物科技股份有限公司 | Use of sitagliptin carboxylic acids and related compounds |
KR102191405B1 (en) * | 2020-09-15 | 2020-12-16 | 주식회사 에이스바이오메드 | Composition for preventing or treating liver diseases |
CN112494471A (en) * | 2020-12-14 | 2021-03-16 | 江南大学 | Application of cholesterol ester synthetase ACAT1 inhibitor in preparing medicine for preventing/treating non-alcoholic fatty liver disease |
KR20230148905A (en) | 2022-04-19 | 2023-10-26 | 한양대학교 산학협력단 | Novel Biomarker for Predicting target group of DPP-4 inhibitor in nonalcoholic fatty liver disease and use thereof |
Citations (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2056046A (en) * | 1933-05-19 | 1936-09-29 | Rhone Poulenc Sa | Manufacture of bases derived from benz-dioxane |
US2375138A (en) * | 1942-05-01 | 1945-05-01 | American Cyanamid Co | Alkamine esters of aryloxymethyl benzoic acid |
US2629736A (en) * | 1951-02-24 | 1953-02-24 | Searle & Co | Basically substituted n-alkyl derivatives of alpha, beta, beta-triarylpropionamides |
US2730544A (en) * | 1952-07-23 | 1956-01-10 | Sahyun Lab | Alkylaminoalkyl esters of hydroxycyclohexylbenzoic acid |
US2750387A (en) * | 1953-11-25 | 1956-06-12 | Searle & Co | Basically substituted derivatives of diarylaminobenzamides |
US2928833A (en) * | 1959-03-03 | 1960-03-15 | S E Massengill Company | Theophylline derivatives |
US3174901A (en) * | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
US3236891A (en) * | 1955-11-29 | 1966-02-22 | Oreal | Nitrophenylenediamine derivatives |
US3454635A (en) * | 1965-07-27 | 1969-07-08 | Hoechst Ag | Benzenesulfonyl-ureas and process for their manufacture |
US3673241A (en) * | 1968-04-04 | 1972-06-27 | Ciba Geigy Corp | Substituted benzaldehyde guanylhydrazones |
US3925357A (en) * | 1972-07-01 | 1975-12-09 | Takeda Chemical Industries Ltd | ' -sulfobenzylpenicillin salt |
US4005208A (en) * | 1975-05-16 | 1977-01-25 | Smithkline Corporation | N-Heterocyclic-9-xanthenylamines |
US4061753A (en) * | 1976-02-06 | 1977-12-06 | Interx Research Corporation | Treating psoriasis with transient pro-drug forms of xanthine derivatives |
US4382091A (en) * | 1981-04-30 | 1983-05-03 | Syntex (U.S.A.) Inc. | Stabilization of 1-substituted imidazole derivatives in talc |
US4599338A (en) * | 1984-01-17 | 1986-07-08 | Adir, S.A.R.L. | Antimigraine 8-[3-(4-aminocarbonyl piperazino and piperidino) propyl[xanthines |
US4639436A (en) * | 1977-08-27 | 1987-01-27 | Bayer Aktiengesellschaft | Antidiabetic 3,4,5-trihydroxypiperidines |
US4687777A (en) * | 1985-01-19 | 1987-08-18 | Takeda Chemical Industries, Ltd. | Thiazolidinedione derivatives, useful as antidiabetic agents |
US4743450A (en) * | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
US4816455A (en) * | 1986-03-21 | 1989-03-28 | Heumann Pharma Gmbh & Co. | Crystalline, anhydrous sigma-form of 2-(4-(2-furoyl)-(2-piperazin)-1-yl)-4-amino-6,7-dimethoxy-quinazoline hydrochloride and a process for its preparation |
US4873330A (en) * | 1984-06-25 | 1989-10-10 | Orion-Yhtyma Oy | A process for the preparation of anhydrous, stable, crystalline delta-form of prazosin hydrochloride |
US4968672A (en) * | 1987-01-02 | 1990-11-06 | The United States Of America As Represented By The Department Of Health And Human Services | Adenosine receptor prodrugs |
US5041448A (en) * | 1985-06-24 | 1991-08-20 | Janssen Pharmaceutica N.V. | (4-piperidinylmethyl and -hetero) purines |
US5051517A (en) * | 1989-05-20 | 1991-09-24 | Bayer Aktiengesellschaft | Process for the preparation of herbicidally active 3-amino-5-aminocarbonyl-1,2,4-triazoles |
US5084460A (en) * | 1990-12-24 | 1992-01-28 | A. H. Robins Company, Incorporated | Methods of therapeutic treatment with N-(3-ouinuclidinyl)-2-hydroxybenzamides and thiobenzamides |
US5130244A (en) * | 1987-08-05 | 1992-07-14 | The Green Cross Corporation | Stable aqueous thrombin solution |
US5164526A (en) * | 1989-10-03 | 1992-11-17 | Biochemie Gesellschaft M.B.H. | Pleuromutilins |
US5219870A (en) * | 1990-02-27 | 1993-06-15 | Kwang Sik Kim | Omeprazole compositions designed for administration in rectum |
US5223499A (en) * | 1989-05-30 | 1993-06-29 | Merck & Co., Inc. | 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists |
US5234897A (en) * | 1989-03-15 | 1993-08-10 | Bayer Aktiengesellschaft | Herbicidal 3-amino-5-aminocarbonyl-1,2,4-triazoles |
US5258380A (en) * | 1985-06-24 | 1993-11-02 | Janssen Pharmaceutica N.V. | (4-piperidinylmethyl and -hetero)purines |
US5266555A (en) * | 1991-07-20 | 1993-11-30 | Bayer Aktiengesellschaft | Substituted triazoles |
US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
US5300298A (en) * | 1992-05-06 | 1994-04-05 | The Pennsylvania Research Corporation | Methods of treating obesity with purine related compounds |
US5329025A (en) * | 1988-09-21 | 1994-07-12 | G. D. Searle & Co. | 3-azido compound |
US5332744A (en) * | 1989-05-30 | 1994-07-26 | Merck & Co., Inc. | Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists |
US5389642A (en) * | 1992-12-16 | 1995-02-14 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Imidazopyridines |
US5399578A (en) * | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
US5407929A (en) * | 1992-07-31 | 1995-04-18 | Shionogi & Co., Ltd. | Triazolylthiomethylthio cephalosporin hydrochhloride, its crystalline hydrate and the production of the same |
US5470579A (en) * | 1989-11-28 | 1995-11-28 | Lvmh, Recherche | Xanthines, optionally incorporated in liposomes, for promoting skin or hair pigmentation |
US5591762A (en) * | 1991-02-06 | 1997-01-07 | Dr. Karl Thomae Gmbh | Benzimidazoles useful as angiotensin-11 antagonists |
US5594003A (en) * | 1991-02-06 | 1997-01-14 | Dr. Karl Thomae Gmbh | Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists |
US5602127A (en) * | 1991-02-06 | 1997-02-11 | Karl Thomae Gmbh | (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists |
US5719279A (en) * | 1992-08-10 | 1998-02-17 | Boehringer Ingelheim Kg | Asymmetrically substituted xanthines |
US5728849A (en) * | 1995-12-22 | 1998-03-17 | Rhone-Poulenc Rorer S.A. | Taxoids their preparation and pharmaceutical compositions containing them |
US5753635A (en) * | 1996-08-16 | 1998-05-19 | Berlex Laboratories, Inc. | Purine derivatives and their use as anti-coagulants |
US5830908A (en) * | 1995-11-22 | 1998-11-03 | Bayer Aktiengesellschaft | Crystalline hydrochloride of (R)-(-)-2-(N- 4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl-)-butyl!-aminomethyl)-chroman |
US5879708A (en) * | 1986-02-13 | 1999-03-09 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US5958951A (en) * | 1996-06-14 | 1999-09-28 | Novo Nordiskials | Modified form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride |
US5965555A (en) * | 1996-06-07 | 1999-10-12 | Hoechst Aktiengesellschaft | Xanthine compounds having terminally animated alkynol side chains |
US6011049A (en) * | 1997-02-19 | 2000-01-04 | Warner-Lambert Company | Combinations for diabetes |
US6107302A (en) * | 1995-01-20 | 2000-08-22 | Glaxo Wellcome Inc. | Guanine derivative |
US6166063A (en) * | 1998-12-10 | 2000-12-26 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6248758B1 (en) * | 1997-03-13 | 2001-06-19 | Hexal Ag | Pharmaceutical antacid |
US20010020006A1 (en) * | 1998-06-24 | 2001-09-06 | Hans-Ulrich Demuth | Compounds of unstable DP IV-inhibitors |
US6303661B1 (en) * | 1996-04-25 | 2001-10-16 | Probiodrug | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
US20010051646A1 (en) * | 2000-03-31 | 2001-12-13 | Hans-Ulrich Demuth | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US6342601B1 (en) * | 1997-12-05 | 2002-01-29 | Astrazeneca Ab | Compounds |
US20020019411A1 (en) * | 2000-03-10 | 2002-02-14 | Robl Jeffrey A. | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US6372940B1 (en) * | 1999-03-19 | 2002-04-16 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A | Process for the preparation of non-hygroscopic salts of L(−)-carnitine |
US20020137903A1 (en) * | 1999-10-12 | 2002-09-26 | Bruce Ellsworth | C-aryl glucoside SGLT2 inhibitors and method |
US20020161001A1 (en) * | 2000-07-04 | 2002-10-31 | Kanstrup Anders Bendtz | Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV |
US20020169174A1 (en) * | 2000-09-19 | 2002-11-14 | Samuel Chackalamannil | Xanthine phosphodiesterase V inhibitors |
US20020198205A1 (en) * | 2001-02-24 | 2002-12-26 | Frank Himmelsbach | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US6548481B1 (en) * | 1998-05-28 | 2003-04-15 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV |
US20030078269A1 (en) * | 2001-03-22 | 2003-04-24 | Chronorx, Llc | Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus |
US20030100563A1 (en) * | 2001-07-06 | 2003-05-29 | Edmondson Scott D. | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US20030105077A1 (en) * | 2001-07-03 | 2003-06-05 | Kanstrup Anders Bendtz | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
US6579868B1 (en) * | 1998-01-05 | 2003-06-17 | Eisai Co., Ltd. | Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes |
US20030114390A1 (en) * | 2001-03-13 | 2003-06-19 | Washburn William N. | C-aryl glucoside SGLT2 inhibitors and method |
US20030130313A1 (en) * | 2000-06-14 | 2003-07-10 | Toshihiro Fujino | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative |
US20030149071A1 (en) * | 2001-12-27 | 2003-08-07 | Gobbi Luca Claudio | Pyrido [2,1-a] isoquinoline derivatives |
US20030166578A1 (en) * | 2000-06-19 | 2003-09-04 | Arch Jonathan Robert Sanders | Combinations od dipeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabetes mellitus |
US20030199528A1 (en) * | 2001-09-19 | 2003-10-23 | Kanstrup Anders B. | Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV |
US20030224043A1 (en) * | 2002-02-01 | 2003-12-04 | Pfizer Inc. | Immediate release dosage forms containing solid drug dispersions |
US20030232987A1 (en) * | 2002-05-31 | 2003-12-18 | Schering Corporation | Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof |
US20030236272A1 (en) * | 2002-01-11 | 2003-12-25 | Carr Richard David | Method and composition for treatment of diabetes, hypertension, chronic heart failure and fluid retentive states |
US20040023981A1 (en) * | 2002-07-24 | 2004-02-05 | Yu Ren | Salt forms with tyrosine kinase activity |
WO2004018468A2 (en) * | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments |
US20040063725A1 (en) * | 2001-01-08 | 2004-04-01 | Martine Barth | Novel n(phenylsulphonyl)glycine derivatives and their therapeutic use |
US20040082570A1 (en) * | 2002-02-25 | 2004-04-29 | Eisai Co., Ltd. | Xanthine derivative and DPPIV inhibitor |
US20040097510A1 (en) * | 2002-08-21 | 2004-05-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US20040116328A1 (en) * | 2002-06-06 | 2004-06-17 | Eisai Co., Ltd. | Condensed imidazole derivatives |
US20040122048A1 (en) * | 2002-10-11 | 2004-06-24 | Wyeth Holdings Corporation | Stabilized pharmaceutical composition containing basic excipients |
US20040122228A1 (en) * | 2002-08-22 | 2004-06-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20040126358A1 (en) * | 2002-09-16 | 2004-07-01 | Warne Nicholas W. | Delayed release formulations for oral administration of a polypeptide therapeutic agent and methods of using same |
US20040138215A1 (en) * | 2002-11-21 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20040138214A1 (en) * | 2002-11-08 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20040152720A1 (en) * | 2002-12-20 | 2004-08-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powdered medicaments containing a tiotropium salt and salmeterol xinafoate |
US20040166125A1 (en) * | 2002-08-22 | 2004-08-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
US6784195B2 (en) * | 2000-02-05 | 2004-08-31 | Vertex Pharmaceuticals Incorporated | Pyrazole compositions useful as inhibitors of ERK |
US20040171836A1 (en) * | 2001-12-21 | 2004-09-02 | Toshihiro Fujino | Method for producing optical-active cis-piperidine derivatives |
US20040259903A1 (en) * | 2003-06-20 | 2004-12-23 | Markus Boehringer | Pyrido [2,1-a] isoquinoline derivatives |
WO2007050485A2 (en) * | 2005-10-25 | 2007-05-03 | Merck & Co., Inc. | Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6861440B2 (en) * | 2001-10-26 | 2005-03-01 | Hoffmann-La Roche Inc. | DPP IV inhibitors |
UY28103A1 (en) * | 2002-12-03 | 2004-06-30 | Boehringer Ingelheim Pharma | NEW IMIDAZO-PIRIDINONAS REPLACED, ITS PREPARATION AND ITS EMPLOYMENT AS MEDICATIONS |
DE602005015699D1 (en) * | 2004-05-12 | 2009-09-10 | Pfizer Prod Inc | PROLIN DERIVATIVES AND THEIR USE AS DIPEPTIDYLPEPTIDASE IV INHIBITORS |
WO2005117861A1 (en) * | 2004-06-04 | 2005-12-15 | Novartis Ag | Use of organic compounds |
DE102004044221A1 (en) * | 2004-09-14 | 2006-03-16 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New 3-methyl-7-butynyl xanthines, their preparation and their use as pharmaceuticals |
BRPI0516340A (en) * | 2004-10-12 | 2008-09-16 | Glenmark Pharmaceuticals Sa | compound, pharmaceutical composition, method for treating a condition that is regulated or normalized via dpp-iv inhibition, method for treating a metabolic disorder, method for treating type ii diabetes, method for lowering blood glucose, method for treating and prophylaxis of a disease, method for treating undamaged insulin-resistant glucose tolerance, method for the manufacture of a pharmaceutical composition and process for the preparation of compounds |
EP1942898B2 (en) * | 2005-09-14 | 2014-05-14 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors for treating diabetes |
WO2007099345A1 (en) * | 2006-03-02 | 2007-09-07 | Betagenon Ab | Medical use of bmp-2 and/ or bmp-4 |
WO2007137107A2 (en) * | 2006-05-19 | 2007-11-29 | Abbott Laboratories | Inhibitors of diacylglycerol o-acyltransferase type 1 enzyme |
WO2007148185A2 (en) * | 2006-06-21 | 2007-12-27 | Pfizer Products Inc. | Substituted 3 -amino- pyrrolidino-4 -lactams as dpp inhibitors |
EP2057160A1 (en) * | 2006-08-08 | 2009-05-13 | Boehringer Ingelheim International GmbH | Pyrrolo [3, 2 -d]pyrimidines as dpp-iv inhibitors for the treatment of diabetes mellitus |
PE20090987A1 (en) * | 2007-08-16 | 2009-08-14 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION INCLUDING A DERIVATIVE OF PIRAZOL-O-GLUCOSIDE |
PE20090938A1 (en) * | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | PHARMACEUTICAL COMPOSITION INCLUDING A BENZENE DERIVATIVE SUBSTITUTED WITH GLUCOPYRANOSIL |
-
2009
- 2009-06-01 PE PE2009000759A patent/PE20100156A1/en not_active Application Discontinuation
- 2009-06-02 EA EA201001860A patent/EA023207B1/en not_active IP Right Cessation
- 2009-06-02 EP EP18151859.8A patent/EP3348263A1/en not_active Withdrawn
- 2009-06-02 WO PCT/EP2009/056722 patent/WO2009147125A1/en active Application Filing
- 2009-06-02 CN CN200980120947.3A patent/CN102056606B/en active Active
- 2009-06-02 KR KR1020167016735A patent/KR101750693B1/en active IP Right Grant
- 2009-06-02 CN CN201310234726.7A patent/CN104013627B/en active Active
- 2009-06-02 KR KR1020107027016A patent/KR20110021835A/en active Application Filing
- 2009-06-02 TW TW098118245A patent/TW201002718A/en unknown
- 2009-06-02 AU AU2009253937A patent/AU2009253937B2/en active Active
- 2009-06-02 MX MX2014002398A patent/MX350455B/en unknown
- 2009-06-02 CA CA2726244A patent/CA2726244C/en not_active Expired - Fee Related
- 2009-06-02 UY UY0001031858A patent/UY31858A/en not_active Application Discontinuation
- 2009-06-02 AR ARP090101984A patent/AR071992A1/en unknown
- 2009-06-02 SG SG2013042668A patent/SG192400A1/en unknown
- 2009-06-02 MX MX2010012270A patent/MX2010012270A/en active IP Right Grant
- 2009-06-02 NZ NZ588843A patent/NZ588843A/en unknown
- 2009-06-02 ES ES09757506.2T patent/ES2660417T3/en active Active
- 2009-06-02 JP JP2011511033A patent/JP2011521003A/en not_active Withdrawn
- 2009-06-02 US US12/995,474 patent/US20110092510A1/en not_active Abandoned
- 2009-06-02 EP EP09757506.2A patent/EP2303262B1/en active Active
-
2010
- 2010-10-19 IL IL208811A patent/IL208811A0/en unknown
- 2010-12-03 CO CO10152516A patent/CO6280472A2/en not_active Application Discontinuation
- 2010-12-03 MA MA33388A patent/MA32372B1/en unknown
- 2010-12-20 EC EC2010010697A patent/ECSP10010697A/en unknown
-
2011
- 2011-06-24 HK HK15101752.9A patent/HK1201195A1/en unknown
-
2013
- 2013-06-06 JP JP2013120060A patent/JP5766749B2/en active Active
-
2014
- 2014-01-28 IL IL230683A patent/IL230683A0/en unknown
Patent Citations (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2056046A (en) * | 1933-05-19 | 1936-09-29 | Rhone Poulenc Sa | Manufacture of bases derived from benz-dioxane |
US2375138A (en) * | 1942-05-01 | 1945-05-01 | American Cyanamid Co | Alkamine esters of aryloxymethyl benzoic acid |
US2629736A (en) * | 1951-02-24 | 1953-02-24 | Searle & Co | Basically substituted n-alkyl derivatives of alpha, beta, beta-triarylpropionamides |
US2730544A (en) * | 1952-07-23 | 1956-01-10 | Sahyun Lab | Alkylaminoalkyl esters of hydroxycyclohexylbenzoic acid |
US2750387A (en) * | 1953-11-25 | 1956-06-12 | Searle & Co | Basically substituted derivatives of diarylaminobenzamides |
US3236891A (en) * | 1955-11-29 | 1966-02-22 | Oreal | Nitrophenylenediamine derivatives |
US2928833A (en) * | 1959-03-03 | 1960-03-15 | S E Massengill Company | Theophylline derivatives |
US3174901A (en) * | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
US3454635A (en) * | 1965-07-27 | 1969-07-08 | Hoechst Ag | Benzenesulfonyl-ureas and process for their manufacture |
US3673241A (en) * | 1968-04-04 | 1972-06-27 | Ciba Geigy Corp | Substituted benzaldehyde guanylhydrazones |
US3925357A (en) * | 1972-07-01 | 1975-12-09 | Takeda Chemical Industries Ltd | ' -sulfobenzylpenicillin salt |
US4005208A (en) * | 1975-05-16 | 1977-01-25 | Smithkline Corporation | N-Heterocyclic-9-xanthenylamines |
US4061753A (en) * | 1976-02-06 | 1977-12-06 | Interx Research Corporation | Treating psoriasis with transient pro-drug forms of xanthine derivatives |
US4639436A (en) * | 1977-08-27 | 1987-01-27 | Bayer Aktiengesellschaft | Antidiabetic 3,4,5-trihydroxypiperidines |
US4382091A (en) * | 1981-04-30 | 1983-05-03 | Syntex (U.S.A.) Inc. | Stabilization of 1-substituted imidazole derivatives in talc |
US4599338A (en) * | 1984-01-17 | 1986-07-08 | Adir, S.A.R.L. | Antimigraine 8-[3-(4-aminocarbonyl piperazino and piperidino) propyl[xanthines |
US4873330A (en) * | 1984-06-25 | 1989-10-10 | Orion-Yhtyma Oy | A process for the preparation of anhydrous, stable, crystalline delta-form of prazosin hydrochloride |
US4687777A (en) * | 1985-01-19 | 1987-08-18 | Takeda Chemical Industries, Ltd. | Thiazolidinedione derivatives, useful as antidiabetic agents |
US5041448A (en) * | 1985-06-24 | 1991-08-20 | Janssen Pharmaceutica N.V. | (4-piperidinylmethyl and -hetero) purines |
US5258380A (en) * | 1985-06-24 | 1993-11-02 | Janssen Pharmaceutica N.V. | (4-piperidinylmethyl and -hetero)purines |
US5879708A (en) * | 1986-02-13 | 1999-03-09 | Takeda Chemical Industries, Ltd. | Stabilized pharmaceutical composition |
US4816455B1 (en) * | 1986-03-21 | 1992-11-24 | Crystalline,anhydrous sigma-form of 2-(4-(2-furoyl)-(2-piperazin)-1-yl)-4-amino-6,7-dimethoxy-quinoazoline hydrochloride and a process for its preparation | |
US4816455A (en) * | 1986-03-21 | 1989-03-28 | Heumann Pharma Gmbh & Co. | Crystalline, anhydrous sigma-form of 2-(4-(2-furoyl)-(2-piperazin)-1-yl)-4-amino-6,7-dimethoxy-quinazoline hydrochloride and a process for its preparation |
US4968672A (en) * | 1987-01-02 | 1990-11-06 | The United States Of America As Represented By The Department Of Health And Human Services | Adenosine receptor prodrugs |
US4743450A (en) * | 1987-02-24 | 1988-05-10 | Warner-Lambert Company | Stabilized compositions |
US5130244A (en) * | 1987-08-05 | 1992-07-14 | The Green Cross Corporation | Stable aqueous thrombin solution |
US5329025A (en) * | 1988-09-21 | 1994-07-12 | G. D. Searle & Co. | 3-azido compound |
US5234897A (en) * | 1989-03-15 | 1993-08-10 | Bayer Aktiengesellschaft | Herbicidal 3-amino-5-aminocarbonyl-1,2,4-triazoles |
US5051517A (en) * | 1989-05-20 | 1991-09-24 | Bayer Aktiengesellschaft | Process for the preparation of herbicidally active 3-amino-5-aminocarbonyl-1,2,4-triazoles |
US5223499A (en) * | 1989-05-30 | 1993-06-29 | Merck & Co., Inc. | 6-amino substituted imidazo[4,5-bipyridines as angiotensin II antagonists |
US5332744A (en) * | 1989-05-30 | 1994-07-26 | Merck & Co., Inc. | Substituted imidazo-fused 6-membered heterocycles as angiotensin II antagonists |
US5273995A (en) * | 1989-07-21 | 1993-12-28 | Warner-Lambert Company | [R-(R*R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl-3-phenyl-4-[(phenylamino) carbonyl]- 1H-pyrrole-1-heptanoic acid, its lactone form and salts thereof |
US5164526A (en) * | 1989-10-03 | 1992-11-17 | Biochemie Gesellschaft M.B.H. | Pleuromutilins |
US5284967A (en) * | 1989-10-03 | 1994-02-08 | Biochemie Gesellschaft M.B.H. | Pleuromutilins |
US5470579A (en) * | 1989-11-28 | 1995-11-28 | Lvmh, Recherche | Xanthines, optionally incorporated in liposomes, for promoting skin or hair pigmentation |
US5965592A (en) * | 1990-02-19 | 1999-10-12 | Novartis Corporation | Acyl compounds |
US5399578A (en) * | 1990-02-19 | 1995-03-21 | Ciba-Geigy Corp | Acyl compounds |
US5219870A (en) * | 1990-02-27 | 1993-06-15 | Kwang Sik Kim | Omeprazole compositions designed for administration in rectum |
US5084460A (en) * | 1990-12-24 | 1992-01-28 | A. H. Robins Company, Incorporated | Methods of therapeutic treatment with N-(3-ouinuclidinyl)-2-hydroxybenzamides and thiobenzamides |
US5591762A (en) * | 1991-02-06 | 1997-01-07 | Dr. Karl Thomae Gmbh | Benzimidazoles useful as angiotensin-11 antagonists |
US5594003A (en) * | 1991-02-06 | 1997-01-14 | Dr. Karl Thomae Gmbh | Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists |
US5602127A (en) * | 1991-02-06 | 1997-02-11 | Karl Thomae Gmbh | (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists |
US5614519A (en) * | 1991-02-06 | 1997-03-25 | Karl Thomae Gmbh | (1-(2,3 or 4-N-morpholinoalkyl)-imidazol-4-yl)-benizimidazol-1-yl-methyl]-biphenyls useful as angiotensin-II antagonists |
US5266555A (en) * | 1991-07-20 | 1993-11-30 | Bayer Aktiengesellschaft | Substituted triazoles |
US5300298A (en) * | 1992-05-06 | 1994-04-05 | The Pennsylvania Research Corporation | Methods of treating obesity with purine related compounds |
US5407929A (en) * | 1992-07-31 | 1995-04-18 | Shionogi & Co., Ltd. | Triazolylthiomethylthio cephalosporin hydrochhloride, its crystalline hydrate and the production of the same |
US5719279A (en) * | 1992-08-10 | 1998-02-17 | Boehringer Ingelheim Kg | Asymmetrically substituted xanthines |
US5389642A (en) * | 1992-12-16 | 1995-02-14 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Imidazopyridines |
US6107302A (en) * | 1995-01-20 | 2000-08-22 | Glaxo Wellcome Inc. | Guanine derivative |
US5830908A (en) * | 1995-11-22 | 1998-11-03 | Bayer Aktiengesellschaft | Crystalline hydrochloride of (R)-(-)-2-(N- 4-(1,1-dioxido-3-oxo-2,3-dihydro-benzisothiazol-2-yl-)-butyl!-aminomethyl)-chroman |
US5728849A (en) * | 1995-12-22 | 1998-03-17 | Rhone-Poulenc Rorer S.A. | Taxoids their preparation and pharmaceutical compositions containing them |
US6303661B1 (en) * | 1996-04-25 | 2001-10-16 | Probiodrug | Use of dipeptidyl peptidase IV effectors for lowering the blood glucose level in mammals |
US5965555A (en) * | 1996-06-07 | 1999-10-12 | Hoechst Aktiengesellschaft | Xanthine compounds having terminally animated alkynol side chains |
US5958951A (en) * | 1996-06-14 | 1999-09-28 | Novo Nordiskials | Modified form of the R(-)-N-(4,4-di(3-methylthien-2-yl)but-3-enyl)-nipecotic acid hydrochloride |
US5753635A (en) * | 1996-08-16 | 1998-05-19 | Berlex Laboratories, Inc. | Purine derivatives and their use as anti-coagulants |
US6011049A (en) * | 1997-02-19 | 2000-01-04 | Warner-Lambert Company | Combinations for diabetes |
US6248758B1 (en) * | 1997-03-13 | 2001-06-19 | Hexal Ag | Pharmaceutical antacid |
US6342601B1 (en) * | 1997-12-05 | 2002-01-29 | Astrazeneca Ab | Compounds |
US6579868B1 (en) * | 1998-01-05 | 2003-06-17 | Eisai Co., Ltd. | Purine derivatives and adenosine A2 receptor antagonists serving as preventives/remedies for diabetes |
US6548481B1 (en) * | 1998-05-28 | 2003-04-15 | Probiodrug Ag | Effectors of dipeptidyl peptidase IV |
US20010020006A1 (en) * | 1998-06-24 | 2001-09-06 | Hans-Ulrich Demuth | Compounds of unstable DP IV-inhibitors |
US6166063A (en) * | 1998-12-10 | 2000-12-26 | Novartis Ag | N-(substituted glycyl)-2-cyanopyrrolidines, pharmaceutical compositions containing them and their use in inhibiting dipeptidyl peptidase-IV |
US6372940B1 (en) * | 1999-03-19 | 2002-04-16 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A | Process for the preparation of non-hygroscopic salts of L(−)-carnitine |
US20020137903A1 (en) * | 1999-10-12 | 2002-09-26 | Bruce Ellsworth | C-aryl glucoside SGLT2 inhibitors and method |
US6784195B2 (en) * | 2000-02-05 | 2004-08-31 | Vertex Pharmaceuticals Incorporated | Pyrazole compositions useful as inhibitors of ERK |
US20020019411A1 (en) * | 2000-03-10 | 2002-02-14 | Robl Jeffrey A. | Cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV and method |
US20010051646A1 (en) * | 2000-03-31 | 2001-12-13 | Hans-Ulrich Demuth | Method for the improvement of islet signaling in diabetes mellitus and for its prevention |
US20030130313A1 (en) * | 2000-06-14 | 2003-07-10 | Toshihiro Fujino | Processes for producing racemic piperidine derivative and for producing optically active piperidine derivative |
US20030166578A1 (en) * | 2000-06-19 | 2003-09-04 | Arch Jonathan Robert Sanders | Combinations od dipeptidyl peptidase iv inhibitors and other antidiabetic agents for the treatment of diabetes mellitus |
US20020161001A1 (en) * | 2000-07-04 | 2002-10-31 | Kanstrup Anders Bendtz | Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV |
US20040034014A1 (en) * | 2000-07-04 | 2004-02-19 | Kanstrup Anders Bendtz | Heterocyclic compounds, which are inhibitors of the enzyme DPP-IV |
US20020169174A1 (en) * | 2000-09-19 | 2002-11-14 | Samuel Chackalamannil | Xanthine phosphodiesterase V inhibitors |
US6821978B2 (en) * | 2000-09-19 | 2004-11-23 | Schering Corporation | Xanthine phosphodiesterase V inhibitors |
US20040063725A1 (en) * | 2001-01-08 | 2004-04-01 | Martine Barth | Novel n(phenylsulphonyl)glycine derivatives and their therapeutic use |
US20040077645A1 (en) * | 2001-02-24 | 2004-04-22 | Frank Himmelsbach | Xanthine derivatives,production and use thereof as medicament |
US20040087587A1 (en) * | 2001-02-24 | 2004-05-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20020198205A1 (en) * | 2001-02-24 | 2002-12-26 | Frank Himmelsbach | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20030114390A1 (en) * | 2001-03-13 | 2003-06-19 | Washburn William N. | C-aryl glucoside SGLT2 inhibitors and method |
US20030078269A1 (en) * | 2001-03-22 | 2003-04-24 | Chronorx, Llc | Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus |
US20030105077A1 (en) * | 2001-07-03 | 2003-06-05 | Kanstrup Anders Bendtz | Heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
US20030100563A1 (en) * | 2001-07-06 | 2003-05-29 | Edmondson Scott D. | Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
US20030199528A1 (en) * | 2001-09-19 | 2003-10-23 | Kanstrup Anders B. | Hetrocyclic compounds that are inhibitors of the enzyme DPP-IV |
US20040171836A1 (en) * | 2001-12-21 | 2004-09-02 | Toshihiro Fujino | Method for producing optical-active cis-piperidine derivatives |
US20030149071A1 (en) * | 2001-12-27 | 2003-08-07 | Gobbi Luca Claudio | Pyrido [2,1-a] isoquinoline derivatives |
US6727261B2 (en) * | 2001-12-27 | 2004-04-27 | Hoffman-La Roche Inc. | Pyrido[2,1-A]Isoquinoline derivatives |
US20030236272A1 (en) * | 2002-01-11 | 2003-12-25 | Carr Richard David | Method and composition for treatment of diabetes, hypertension, chronic heart failure and fluid retentive states |
US20030224043A1 (en) * | 2002-02-01 | 2003-12-04 | Pfizer Inc. | Immediate release dosage forms containing solid drug dispersions |
US20040082570A1 (en) * | 2002-02-25 | 2004-04-29 | Eisai Co., Ltd. | Xanthine derivative and DPPIV inhibitor |
US20030232987A1 (en) * | 2002-05-31 | 2003-12-18 | Schering Corporation | Process for preparing xanthine phosphodiesterase V inhibitors and precursors thereof |
US20040116328A1 (en) * | 2002-06-06 | 2004-06-17 | Eisai Co., Ltd. | Condensed imidazole derivatives |
US20040023981A1 (en) * | 2002-07-24 | 2004-02-05 | Yu Ren | Salt forms with tyrosine kinase activity |
US20040097510A1 (en) * | 2002-08-21 | 2004-05-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
WO2004018468A2 (en) * | 2002-08-21 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the production thereof and the use of the same as medicaments |
US20040122228A1 (en) * | 2002-08-22 | 2004-06-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New purine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20040166125A1 (en) * | 2002-08-22 | 2004-08-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, their preparation and their use in pharmaceutical compositions |
US20040126358A1 (en) * | 2002-09-16 | 2004-07-01 | Warne Nicholas W. | Delayed release formulations for oral administration of a polypeptide therapeutic agent and methods of using same |
US20040122048A1 (en) * | 2002-10-11 | 2004-06-24 | Wyeth Holdings Corporation | Stabilized pharmaceutical composition containing basic excipients |
US20040138214A1 (en) * | 2002-11-08 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20040138215A1 (en) * | 2002-11-21 | 2004-07-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Xanthine derivatives, the preparation thereof and their use as pharmaceutical compositions |
US20040152720A1 (en) * | 2002-12-20 | 2004-08-05 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powdered medicaments containing a tiotropium salt and salmeterol xinafoate |
US20040259903A1 (en) * | 2003-06-20 | 2004-12-23 | Markus Boehringer | Pyrido [2,1-a] isoquinoline derivatives |
WO2007050485A2 (en) * | 2005-10-25 | 2007-05-03 | Merck & Co., Inc. | Combination of a dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension |
Non-Patent Citations (10)
Title |
---|
Balaban et al (2007). "Dipeptidyl peptidase IV (DDP IV) in NASH patients". Annals of Hepatology, 6(4): 242-250. * |
Boulton et al (June 2007). "Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Once-Daily Oral Doses of Saxagliptin for 2 Weeks in Type 2 Diabetic and Healthy Subjects." Diabetes, 1(56): pA161-A161; abstract only. * |
Craddy et al (2014). "Comparative effective of dipeptidylpeptidase-4 inhibitors in type 2 diabetes: a systemic review and mixed treatment comparison." Diabetes Ther., 5(1): 1-41. * |
Diabetesincontrol.com.(originally posted 25 September 2007) [retrieved on 2012 November 30]. Retrieved from the Internet: . * |
Fiorucci et al (27 June 2007). "Targeting farnesoid X receptor for liver and metabolic disorders." TRENDS in Molecular Medicine, 13(7): 298-309. * |
Gupta et al (2011). "Choosing a Gliptin." Indian J Endocrinol Metab., 15(4): 298-308. * |
Machine Translation of WO 2004018468 A2 * |
Mayo Clinic Staff. "Nonalcoholic fatty liver disease: Prevention" [retrieved on 2012 November 30]. Retrieved from the Internet: ) * |
Shanks et al. (2009). "Are animal models predictive for humans?". Philosophy, Ethics, and Humanities in Medicine, 4(2): 1-20. * |
Targher et al (2007). "Prevalence of Nonalcoholic Fatty Liver Disease and Its Association with Cardiovascular Disease Among Type 2 Diabetic Patients". Diabetes Care, 30(5): 1212-1218. * |
Cited By (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8664232B2 (en) | 2002-08-21 | 2014-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10202383B2 (en) | 2002-08-21 | 2019-02-12 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8178541B2 (en) | 2002-08-21 | 2012-05-15 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US10023574B2 (en) | 2002-08-21 | 2018-07-17 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9108964B2 (en) | 2002-08-21 | 2015-08-18 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9556175B2 (en) | 2002-08-21 | 2017-01-31 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and thier use as pharmaceutical compositions |
US8119648B2 (en) | 2002-08-21 | 2012-02-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US9321791B2 (en) | 2002-08-21 | 2016-04-26 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
US8697868B2 (en) | 2004-02-18 | 2014-04-15 | Boehringer Ingelheim International Gmbh | 8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions |
US9499546B2 (en) | 2004-11-05 | 2016-11-22 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US8883805B2 (en) | 2004-11-05 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US8541450B2 (en) | 2004-11-05 | 2013-09-24 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1yl)-xanthines |
US9751855B2 (en) | 2004-11-05 | 2017-09-05 | Boehringer Ingelheim International Gmbh | Process for the preparation of chiral 8-(3-aminopiperidin-1-yl)-xanthines |
US8637530B2 (en) | 2005-07-30 | 2014-01-28 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US8106060B2 (en) | 2005-07-30 | 2012-01-31 | Boehringer Ingelheim International Gmbh | 8-(3-amino-piperidin-1-yl)-xanthines, their preparation, and their use as pharmaceuticals |
US9493462B2 (en) | 2006-05-04 | 2016-11-15 | Boehringer Ingelheim International Gmbh | Polymorphs |
US11919903B2 (en) | 2006-05-04 | 2024-03-05 | Boehringer Ingelheim International Gmbh | Polymorphs |
US8232281B2 (en) | 2006-05-04 | 2012-07-31 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US9815837B2 (en) | 2006-05-04 | 2017-11-14 | Boehringer Ingelheim International Gmbh | Polymorphs |
US10080754B2 (en) | 2006-05-04 | 2018-09-25 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US10301313B2 (en) | 2006-05-04 | 2019-05-28 | Boehringer Ingelheim International Gmbh | Polymorphs |
US8673927B2 (en) | 2006-05-04 | 2014-03-18 | Boehringer Ingelheim International Gmbh | Uses of DPP-IV inhibitors |
US9173859B2 (en) | 2006-05-04 | 2015-11-03 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US11033552B2 (en) | 2006-05-04 | 2021-06-15 | Boehringer Ingelheim International Gmbh | DPP IV inhibitor formulations |
US11291668B2 (en) | 2006-05-04 | 2022-04-05 | Boehringer Ingelheim International Gmbh | Uses of DPP IV inhibitors |
US11084819B2 (en) | 2006-05-04 | 2021-08-10 | Boehringer Ingelheim International Gmbh | Polymorphs |
US9266888B2 (en) | 2006-05-04 | 2016-02-23 | Boehringer Ingelheim International Gmbh | Polymorphs |
US8551957B2 (en) | 2007-08-16 | 2013-10-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate |
US10881714B2 (en) | 2008-03-26 | 2021-01-05 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
US11660327B2 (en) | 2008-03-26 | 2023-05-30 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
US10058593B2 (en) | 2008-03-26 | 2018-08-28 | Oramed Ltd. | Methods and compositions for oral administration of proteins |
US9415016B2 (en) | 2008-04-03 | 2016-08-16 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10022379B2 (en) | 2008-04-03 | 2018-07-17 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US9155705B2 (en) | 2008-04-03 | 2015-10-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10973827B2 (en) | 2008-04-03 | 2021-04-13 | Boehringer Ingelheim International Gmbh | DPP-IV inhibitor combined with a further antidiabetic agent, tablets comprising such formulations, their use and process for their preparation |
US10034877B2 (en) | 2008-08-06 | 2018-07-31 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8853156B2 (en) | 2008-08-06 | 2014-10-07 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US9486526B2 (en) | 2008-08-06 | 2016-11-08 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients inappropriate for metformin therapy |
US8513264B2 (en) | 2008-09-10 | 2013-08-20 | Boehringer Ingelheim International Gmbh | Combination therapy for the treatment of diabetes and related conditions |
US11911388B2 (en) | 2008-10-16 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
US9212183B2 (en) | 2008-12-23 | 2015-12-15 | Boehringer Ingelheim International Gmbh | Salt forms of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine |
US8865729B2 (en) | 2008-12-23 | 2014-10-21 | Boehringer Ingelheim International Gmbh | Salt forms of a xanthine compound |
US8846695B2 (en) | 2009-01-07 | 2014-09-30 | Boehringer Ingelheim International Gmbh | Treatment for diabetes in patients with inadequate glycemic control despite metformin therapy comprising a DPP-IV inhibitor |
US10406172B2 (en) | 2009-02-13 | 2019-09-10 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US10092571B2 (en) | 2009-11-27 | 2018-10-09 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9457029B2 (en) | 2009-11-27 | 2016-10-04 | Boehringer Ingelheim International Gmbh | Treatment of genotyped diabetic patients with DPP-IV inhibitors such as linagliptin |
US9603851B2 (en) | 2010-05-05 | 2017-03-28 | Boehringer Ingelheim International Gmbh | Combination therapy |
US10004747B2 (en) | 2010-05-05 | 2018-06-26 | Boehringer Ingelheim International Gmbh | Combination therapy |
US9186392B2 (en) | 2010-05-05 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Combination therapy |
US9149478B2 (en) | 2010-06-24 | 2015-10-06 | Boehringer Ingelheim International Gmbh | Diabetes therapy |
US9034883B2 (en) | 2010-11-15 | 2015-05-19 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US11911387B2 (en) | 2010-11-15 | 2024-02-27 | Boehringer Ingelheim International Gmbh | Vasoprotective and cardioprotective antidiabetic therapy |
US11564886B2 (en) | 2011-03-07 | 2023-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
US10596120B2 (en) | 2011-03-07 | 2020-03-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
US20180185291A1 (en) | 2011-03-07 | 2018-07-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions |
US9199998B2 (en) | 2011-07-15 | 2015-12-01 | Boehringer Ingelheim Internatioal Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US8962636B2 (en) | 2011-07-15 | 2015-02-24 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US8883800B2 (en) | 2011-07-15 | 2014-11-11 | Boehringer Ingelheim International Gmbh | Substituted quinazolines, the preparation thereof and the use thereof in pharmaceutical compositions |
US20130244932A1 (en) * | 2012-02-24 | 2013-09-19 | Wisconsin Alumni Research Foundation | E-prostanoid receptor, ptger3, as a novel anti-diabetic therapeutic target |
US9381176B2 (en) * | 2012-02-24 | 2016-07-05 | Wisconsin Alumni Research Foundation | E-prostanoid receptor, Ptger3, as a novel anti-diabetic therapeutic target |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9526730B2 (en) | 2012-05-14 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US10195203B2 (en) | 2012-05-14 | 2019-02-05 | Boehringr Ingelheim International GmbH | Use of a DPP-4 inhibitor in podocytes related disorders and/or nephrotic syndrome |
US9713618B2 (en) | 2012-05-24 | 2017-07-25 | Boehringer Ingelheim International Gmbh | Method for modifying food intake and regulating food preference with a DPP-4 inhibitor |
US20150335715A1 (en) * | 2013-01-03 | 2015-11-26 | Oramed Ltd. | Methods and compositions for treating nafld, hepatic steatosis, and sequelae thereof |
US10967051B2 (en) | 2013-01-03 | 2021-04-06 | Oramed Ltd. | Methods and compositions for treating NAFLD, hepatic steatosis, and sequelae thereof |
US9526728B2 (en) | 2014-02-28 | 2016-12-27 | Boehringer Ingelheim International Gmbh | Medical use of a DPP-4 inhibitor |
EA023747B1 (en) * | 2014-11-13 | 2016-07-29 | Промомед Холдингс Лимитед | Pharmaceutical composition for preventing and treating overweight or obesity related disorders (variants), kits (variants), use thereof and method of preventing and treating overweight or obesity related disorders |
WO2016085994A1 (en) * | 2014-11-26 | 2016-06-02 | Medicinova, Inc. | Ibudilast and telmisartan for treating non-alcoholic fatty liver disease, non alcoholic steatohepatitis, and advanced non alcoholic steatohepatitis |
US10906881B2 (en) | 2015-11-09 | 2021-02-02 | Cortexyme, Inc. | Inhibitors of arginine gingipain |
WO2017083433A1 (en) * | 2015-11-09 | 2017-05-18 | Cortexyme, Inc. | Inhibitors of arginine gingipain |
US10155000B2 (en) | 2016-06-10 | 2018-12-18 | Boehringer Ingelheim International Gmbh | Medical use of pharmaceutical combination or composition |
US10857136B2 (en) | 2017-03-14 | 2020-12-08 | Sjt Molecular Research, Sl | Compounds for use in the prevention and/or treatment of non-alcoholic fat liver disease and non-alcoholic steatohepatitis |
WO2020236890A1 (en) * | 2019-05-20 | 2020-11-26 | Mayo Foundation For Medical Education And Research | Treating chronic liver disease |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2303262B1 (en) | Dpp-iv inhibitors for use in the treatment of nafld | |
US20170368068A1 (en) | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug | |
US20220323434A1 (en) | Treatment for diabetes in patients inappropriate for metformin therapy | |
US20160206620A1 (en) | Purin derivatives for use in the treatment of fab-related diseases | |
US10034877B2 (en) | Treatment for diabetes in patients inappropriate for metformin therapy | |
US20110263617A1 (en) | Combination therapy for the treatment of diabetes and related conditions | |
JP2012505859A6 (en) | Treatment of diabetes in patients with insufficient glycemic control despite treatment with oral or parenteral antidiabetic drugs | |
US11911388B2 (en) | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug | |
KR20240046643A (en) | Treatment for diabetes in patients with insufficient glycemic control despite therapy with an oral or non-oral antidiabetic drug |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: BOEHRINGER INGELHEIM INTERNATIONAL GMBH, GERMANY Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:KLEIN, THOMAS;MARK, MICHAEL;NIESSEN, HEIKO;AND OTHERS;REEL/FRAME:025596/0751 Effective date: 20101209 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |